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EDITOR,-E A Benson suggests that tumours over 2 cm in size should not be treated by breast conservation surgery because they seem to be associated with an increased risk of local recurrence. 1 To support this Benson reports data from Nottingham. 2 In a comprehensive review of factors affecting local recurrence after breast conservation (wide excision and quadrantectomy and postoperative radiotherapy) we have identified 28 publications that have correlated tumour size and local recurrence.

Objective: The aim of this study was to describe the pharmacokinetics of 3 different single doses of fulvestrant—a new estrogen receptor (ER) antagonist that downregulates the ER with no known agonist effects—administered as a prolonged-release IM formulation. Methods: Pharmacokinetic data were obtained in a randomized, partially blinded, placebo-controlled, parallel-group, Phase I/II multicenter trial involving postmenopausal women with primary breast cancer (clinical stages T1–T3, with tumors that were ER positive or of unknown ER status) awaiting curative-intent surgery. Patients received either IM fulvestrant (50, 125, or 250 mg), oral tamoxifen (20 mg, once daily), or oral placebo (once daily). Treatment started 2 to 3 weeks before surgery and blood was taken at various times up to 12 weeks after fulvestrant administration to assess pharmacokinetic variables. Results: A total of 200 patients entered the trial, of whom 58 took part in the pharmacokinetic analysis (50 mg, n = 20; 125 mg, n = 16; 250 mg, n = 22). Following single IM injections of fulvestrant, the median time to maximum concentration was 6.98, 6.98, and 6.96 days in the 50-, 125,- and 250-mg dose groups, respectively, with an overall range of 2 to 19 days). The plasma concentration-time profiles were primarily controlled by the rate of absorption from the injection site; post-peak plasma concentrations declined over time and were measurable up to 84 days after administration of fulvestrant 125 and 250 mg. Plasma

For invasive breast cancer, sentinel node biopsy (SNB) is an acceptable alternative to axillary node clearance (ANC), although in the recent era, its role is under review. In ductal carcinoma in situ (DCIS), the benefit of SNB is even less well defined. Despite this, guidelines still recommend that it is performed in selected cases of DCIS. The aim of our study was to evaluate the diagnostic value of performing SNB in DCIS. Patients with a diagnosis of DCIS who underwent axillary staging with SNB between 2008-2019 in our large volume tertiary centre were identified and included in the study. Out of the 48 patients who were identified, four patients had a positive SNB (8%). Two of those patients were found to have micro metastatic disease. None of the patients with a positive SNB had local or systemic recurrence (median follow up: 40 months). One non-breast cancer-related mortality was reported. Two patients were identified who had recurrent disease, one with an invasive recurrence in the breast, and the other with systemic recurrence in the form of bone disease. Both of these patients had a negative SNB. Our results confirm that performing axillary staging with SNB in DCIS is not justifiable, as it does not affect patient outcomes. This supports the emerging evidence that being more surgically conservative may decrease morbidity without affecting patient survival.

The aim of the present study was to assess the sensitivity, specificity and practicality of using a one-step nucleic acid amplification (OSNA) assay during breast cancer staging surgery to predict and discriminate between at least 2 involved nodes and more than 2 involved nodes and facilitate the decision to provide axillary conservation in the presence of a low total axillary node tumour burden. A total of 700 consecutive patients, not treated with neo-adjuvant chemotherapy, received intraoperative sentinel lymph node (SLN) analysis using OSNA for cT1-T3 cN0 invasive breast cancer. Patients with at least one macrometastasis on whole-node SLN analysis underwent axillary lymph node dissection (ALND). The total tumour load (TTL) of the macrometastatic SLN sample was compared with the non-sentinel lymph node (NSLN) status of the ALND specimen using routine histological assessment. In total, 122/683 patients (17.9%) were found to have an OSNA TTL indicative of macrometastasis. In addition, 45/122 (37%) patients had NSLN metastases on ALND with a total positive lymph node burden exceeding the American College of Surgeons Oncology Group Z0011 trial threshold of two macrometastatic nodes. The TTL negative predictive value was 0.975 [95% confidence interval (CI), 0.962-0.988]. The area under the curve for the receiver operating characteristic curve was 0.86 (95% CI, 0.81-0.91), indicating that SLN TTL was associated with the prediction (and partitioning) of total axillary disease burden. OSNA identifies a TTL threshold value where, in the presence of involved SLNs, ALND may be avoided. This technique offers objective confidence in adopting conservative management of the axilla in patients with SLN macrometastases.

Avoiding axillary node clearance in patients with early stage breast cancer and low-burden node-positive axillary disease is an emerging practice. Informing the decision to adopt axillary conservation is examined by comparing routine preoperative axillary staging using ultrasound (AUS) ± AUS biopsy (AUSB) with intraoperative staging using sentinel lymph node biopsy (SLNB) and a one-step nucleic acid cytokeratin-19 amplification assay (OSNA). A single-centre, retrospective cohort study of 1,315 consecutive new diagnoses of breast cancer in 1,306 patients was undertaken in the present study. An AUS ± AUSB was performed on all patients as part of their initial assessment. Patients who had a normal ultrasound (AUS-) or negative biopsy (AUSB-) followed by SLNB with OSNA ± axillary lymph node dissection (ALND), and those with a positive AUSB (AUSB+), were assessed. Tests for association were determined using a χ2 and Fisher's Exact test. A total of 266 (20.4%) patients with cT1-3 cN0 staging received 271 AUSBs. Of these, 205 biopsies were positive and 66 were negative. The 684 patients with an AUS-/AUSB-assessment proceeded to SLNB with OSNA. AUS sensitivity and negative predictive value (NPV) were 0.53 [0.44-0.62; 95% confidence interval (CI)] and 0.58 (0.53-0.64, 95% CI), respectively. Using a total tumour load cut-off of 15,000 copies/µl to predict ≥2 macro-metastases, the sensitivity and NPV for OSNA were 0.82 (0.71-0.92, 95% CI) and 0.98 (0.97-0.99, 95% CI) (OSNA vs. AUS P<0.0001). Of the AUSB+ patients, 51% had ≤2 positive nodes following ALND and were potentially over-treated. Where available, SLNB with OSNA should replace AUSB for axillary assessment in cT1-2 cN0 patients with ≤2 indeterminate nodes seen on AUS.

Single cardiac ATP-sensitive K+ channels and, comparatively, two other members of the inwardly rectifying K+ channel family, cardiac K+(ir) and K+(ACh) channels, were studied in the inside-out recording mode in order to analyze influence and significance of the electrochemical K+ gradient for open-state kinetics of these K+ channels. The conductive state of K+(ATP) channels was defined as a function of the electrochemical K+ gradient in that increased driving force correlates with shortened open-channel lifetime. Flux coupling of gating can be largely excluded as the underlying mechanism for two reasons: (i) tauopen proved identical in 23 pS, 56 pS and 80 pS channels; (ii) K+(ATP) channel protonation by an external pH shift from 9.5 to 5.5 reduced conductance without a concomitant detectable change of tauopen. Since gating continued to operate at EK, i.e., in the absence of K+ permeation through the pore, K+ driving force cannot be causally involved in gating. Rather the driving force acts to modulate the gating process similar to Rb+ whose interference with an externally located binding site stabilizes the open state. In K+(ir) and K+(ACh) channels, the open state is essentially independent on driving force meaning that their gating apparatus does not sense the electrochemical K+ gradient. Thus, K+(ATP) channels differ in an important functional aspect which may be tentatively explained by a structural peculiarity of their gating apparatus.

A member of the family of Ca(++)-independent large conductance K+ channels (termed BK channels) was identified in patch clamp experiments with cultured neonatal rat hippocampal neurons. Permeation was characterized (at 5 mmol/l external, 140 mmol/l internal K+; 135 mmol/l external Na+) by a conductance of 107 pS, a ratio PNa/Pk approximately 0.01, and outward rectification near the reversal potential. Channel activity was not voltage-dependent, could not be reduced by internal TEA or by a shift of internal pH from 7.4 to 6.8, i.e., discriminating features within the Ca(++)-independent BK channel family. Cytosolic proteolysis abolished the functional state of hippocampal Ca(++)-independent BK channels, in contrast to the pronase resistance of hippocampal Ca(++)-activated BK channels which suggests structural dissimilarities between these related channels. Cytoskeletal alterations had an activating influence on Ca(++)-independent BK channels and caused a 3-4-fold rise in Po, but patch excision and channel isolation from the natural environment provoked the strongest increase in Po, from 0.07 +/- 0.03 to 0.73 +/- 0.04. This activation process operated slowly, on a minute time scale and can be most easily explained with the loss of a membrane-associated inhibitory particle. Once activated, Ca(++)-independent BK channels reacted sensitively to a Mg-ATP supplemented brain tissue extract with a Po decline, from 0.60 +/- 0.06 to 0.10 +/- 0.05. Heated extracts failed to induce significant channel inhibition, providing evidence for a heat-unstable molecule with reassociates with the internal channel surface to reestablish channel inhibition. A dualistic channel control, by this membrane-associated molecule and by the cytoskeleton seems possible.

Failure of inactivation is the typical response of voltage-gated Na+ channels to the cytosolic presence of proteolytic enzymes, protein reagents such as N-bromoacetamide (NBA) or iodate, and antibodies directed against the linker between domains III and IV of the alpha-subunit. The present patch clamp experiments with cardiac Na+ channels aimed to test the hypothesis that these interventions may provoke the occurrence of non-inactivating Na+ channels with distinct kinetic properties. A site-directed polyclonal antibody (anti-SLP2, target sequence 1481-1496 of the cardiac Na+ channel alpha-subunit) eliminated fast Na+ inactivation to induce burst activity which was accompanied by the occurrence of two open states. A deactivation process terminated channel activity during membrane depolarization proceeding with time constants of close to 40 ms (at -40 mV). NBA-modified and iodatemodified Na+ channels were kinetically indistinguishable from the anti-SLP2-modified type since they likewise deactivate and, thus, attain an only moderate Po of close to 20%. This is fundamentally different from the behaviour of enzymatically-modified Na+ channels: after cytosolic proteolysis with alpha-chymotrypsin, trypsin or pronase, mean Po during membrane depolarization amounted to approximately 40% because deactivation operated extremely slowly and less efficiently (time constants 100-200 ms at -40 mV, as a minimum) or was virtually non-operating. Invitro cleavage of the synthetic linker sequence 1481-1496 confirmed that this part of the alpha-subunit provides a substrate for these peptidases or reactants for NBA but cannot be chemically modified by iodate. This iodate resistance indicates that iodate-modified Na+ channels are based on a structural alteration of still another region which is also involved in Na+ inactivation, besides the linker between domains III and IV of the alpha-subunit. Endogenous peptidases such as calpain did not affect Na+ inactivation. This stresses the stochastic nature of a kinetic peculiarity of cardiac Na+ channels, mode-switching to a non-inactivating mode.