The long-term survival rate among women who undergo breast-conserving surgery is the same as that among women who undergo radical mastectomy. Breast-conserving surgery is therefore the treatment of choice for women with relatively small breast cancers.

Sentinel-node biopsy is a safe and accurate method of screening the axillary nodes for metastasis in women with a small breast cancer.

In the large majority of patients with breast cancer, lymphoscintigraphy and gamma-probe-guided surgery can be used to locate the sentinel node in the axilla, and thereby provide important information about the status of axillary nodes. Patients without clinical involvement of the axilla should undergo sentinel-node biopsy routinely, and may be spared complete axillary dissection when the sentinel node is disease-free.

Background For breast cancer patients with a metastatic sentinel node (SN), axillary dissection (AD) has been standard treatment. However, for patients with minimal SN involvement, AD may be overtreatment. IBCSG Trial 23-01 was designed to determine whether no AD is non-inferior to AD in patients with one or more micrometastatic (≤2 mm) SNs and tumour ≤5 cm. Methods In this multicentre trial patients were randomised to AD or no AD. Eligibility was limited to patients with clinically-palpable axillary lymph node(s) and a primary tumour ≤ 5 cm who, after sentinel node biopsy, had one or more micrometastatic (≤ 2 mm) sentinel lymphs nodes with no extracapsular extension. The primary endpoint was disease-free survival (DFS). Non-inferiority was defined as a hazard ratio of <1·25 for no AD vs. AD. The analysis was intention to treat. Patients were randomly allocated in a 1:1 ratio to AD or no AD with stratification by centre and menopausal status. There was no attempt to blind the treatment assignment. The trial is registered with ClinicalTrials.gov, NCT00072293. Per protocol, disease and survival information continues to be collected yearly. Findings From 2001 to 2010, 934 patients were randomised; 931 were evaluable (464 in the AD group and 467 in the no AD group). After a median follow-up of 5·0 (IQR 3.6–7.3) years, there were 124 DFS events, including breast-cancer-related events in 95 patients (local, 18; contralateral breast, 12; regional, 6; and distant, 59), and other events in 29 (second malignancy, 26; death without prior cancer event, 3). Five-year DFS was 87·8% (95% CI 84·4%–91·2%) in the no AD group and 84·4% (95% CI 80·7%–88·1%) in the AD group (log-rank p=0·16) (HR no AD vs. AD=0·78, 95% CI 0·55–1·11, non-inferiority p=0·0042). Patients with reported long-term surgical events (grade 3–4) included 1 sensory neuropathy (grade 3), 3 lymphedema (2 grade 3 and 1 grade 4), and 3 motor neuropathy (grade 3), all in the AD group, and 1 grade 3 motor neuropathy in the no AD group. One serious adverse event was reported, a post-operative infection in the axilla in the AD group. Interpretation AD in patients with early breast cancer represented in this study (most had tumours < 3 cm (92%; 856/931), received breast conserving surgery (91%; 845/931) and adjuvant systemic therapy (96%; 892/931)) should be avoided when the SN is minimally involved, thus eliminating complications of axillary surgery with no adverse effect on survival. Funding Supported in part: local participating centres, IBCSG central funds, CA075362 from the U.S. National Cancer Institute, and Swiss Cancer League/Cancer Research- Switzerland/Oncosuisse (ICPOCS 01688-03-2005). No pharmaceutical company funds were used.

No abstract

The small GTPase ADP-ribosylation factor (ARF) regulates the structure and function of the Golgi complex through mechanisms that are understood only in part, and which include an ability to control the assembly of coat complexes and phospholipase D (PLD). Here we describe a new property of ARF, the ability to recruit phosphatidylinositol-4-OH kinase-beta and a still unidentified phosphatidylinositol-4-phosphate-5-OH kinase to the Golgi complex, resulting in a potent stimulation of synthesis of phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate; this ability is independent of its activities on coat proteins and PLD. Phosphatidylinositol-4-OH kinase-beta is required for the structural integrity of the Golgi complex: transfection of a dominant-negative mutant of the kinase markedly alters the organization of the organelle.

From 1973 to 1980, we carried out a controlled study at the National Cancer Institute in Milan to consider the value of a conservative procedure in patients with breast cancer of small size. We randomized 701 patients with breast cancer measuring less than 2 cm in diameter and with no palpable axillary lymph nodes to Halsted radical mastectomy or to "quadrantectomy" with axillary dissection and radiotherapy to the ipsilateral residual breast tissue. We treated 349 patients with Halsted mastectomy and 352 with quadrantectomy. The two groups were comparable in age distribution, size and site of primary tumor, menopausal status, and frequency of axillary metastases. There were three local recurrences in the Halsted group and one in the quadrantectomy group. Actuarial curves showed no difference between the two groups in disease-free or overall survival. From these results, mastectomy appears to involve unnecessary mutilation in patients with breast cancer of less than 2 cm and no palpable axillary nodes.

The organization and mutual interactions between endoplasmic reticulum (ER) and mitochondria modulate key aspects of cell pathophysiology. Several proteins have been suggested to be involved in keeping ER and mitochondria at a correct distance. Among them, in mammalian cells, mitofusin 2 (Mfn2), located on both the outer mitochondrial membrane and the ER surface, has been proposed to be a physical tether between the two organelles, forming homotypic interactions and heterocomplexes with its homolog Mfn1. Recently, this widely accepted model has been challenged using quantitative EM analysis. Using a multiplicity of morphological, biochemical, functional, and genetic approaches, we demonstrate that Mfn2 ablation increases the structural and functional ER-mitochondria coupling. In particular, we show that in different cell types Mfn2 ablation or silencing increases the close contacts between the two organelles and strengthens the efficacy of inositol trisphosphate (IP3)-induced Ca 2+ transfer from the ER to mitochondria, sensitizing cells to a mitochondrial Ca 2+ overload-dependent death. We also show that the previously reported discrepancy between electron and fluorescence microscopy data on ER-mitochondria proximity in Mfn2-ablated cells is only apparent. By using a different type of morphological analysis of fluorescent images that takes into account (and corrects for) the gross modifications in mitochondrial shape resulting from Mfn2 ablation, we demonstrate that an increased proximity between the organelles is also observed by confocal microscopy when Mfn2 levels are reduced. Based on these results, we propose a new model for ER-mitochondria juxtaposition in which Mfn2 works as a tethering antagonist preventing an excessive, potentially toxic, proximity between the two organelles. mitofusin 2 | ER-mitochondria tethering | inter-organellar communication D uring the last decade, evidence has accumulated showing the existence of a continuous flux of information between the endoplasmic reticulum (ER) and mitochondria, two organelles whose privileged interplay is essential, e.g., for lipid metabolism and modulation of Ca 2+ signaling (1, 2). As to the former, Vance (3) firstly described a partially purified microsomal subfraction pulled down with mitochondria (fraction X, later renamed "mitochondria-associated membrane," MAM) that was found to be enriched in phosphatidylserine synthase and several enzymes involved in lipid and glucose metabolism, cholesterol, and ceramide biosynthesis (4, 5). As far as Ca 2+ signaling is concerned, the ERmitochondria axis plays a critical role in cell Ca 2+ homeostasis (6-8). In parallel, increases of Ca 2+ within mitochondria are essential in tuning physiological organelle activity (9, 10) and in modulating the process of cell death (6,8,11). ER-mitochondria connections and Ca 2+ signals are also critical for mitochondrial fission (12, 13), for autophagosome generation (14), and for the removal of damaged mitochondria by autophagy (15).Several proteins have been suggested to be ...