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INTRODUCTION: Despite national guidelines and use of intrapartum antibiotic prophylaxis (IAP), Streptococcus agalactiae (group B streptococci (GBS)) is still a leading cause of morbidity and mortality in newborns in Europe and the United States. The European DEVANI (Design of a Vaccine Against Neonatal Infections) program assessed the neonatal GBS infection burden in Europe, the clinical characteristics of colonized women and microbiological data of GBS strains in colonized women and their infants with early-onset disease (EOD). METHODS: Overall, 1083 pregnant women with a GBS-positive culture result from eight European countries were included in the study. Clinical obstetrical information was collected by a standardized questionnaire. GBS strains were characterized by serological and molecular methods. RESULTS: Among GBS carriers included in this study after testing positive for GBS by vaginal or recto-vaginal sampling, 13.4% had at least one additional obstetrical risk factor for EOD. The five most common capsular types (i.e., Ia, Ib, II, III and V) comprised ~ 93% of GBS carried. Of the colonized women, 77.8% received any IAP, and in 49.5% the IAP was considered appropriate. In our cohort, nine neonates presented with GBS early-onset disease (EOD) with significant regional heterogeneity. CONCLUSIONS: Screening methods and IAP rates need to be harmonized across Europe in order to reduce the rates of EOD. The epidemiological data from eight different European countries provides important information for the development of a successful GBS vaccine.

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OBJECTIVES: Corneal diseases are among the main causes of blindness, with approximately 4.6 and 23 million patients worldwide suffering from bilateral and unilateral corneal blindness, respectively. The standard treatment for severe corneal diseases is corneal transplantation. However, relevant disadvantages, particularly in high-risk conditions, have focused the attention on the search for alternatives. METHODS: We report interim findings of a phase I-II clinical study evaluating the safety and preliminary efficacy of a tissue-engineered corneal substitute composed of a nanostructured fibrin-agarose biocompatible scaffold combined with allogeneic corneal epithelial and stromal cells (NANOULCOR). 5 subjects (5 eyes) suffering from trophic corneal ulcers refractory to conventional treatments, who combined stromal degradation or fibrosis and limbal stem cell deficiency, were included and treated with this allogeneic anterior corneal substitute. RESULTS: The implant completely covered the corneal surface, and ocular surface inflammation decreased following surgery. Only four adverse reactions were registered, and none of them were severe. No detachment, ulcer relapse nor surgical re-interventions were registered after 2 years of follow-up. No signs of graft rejection, local infection or corneal neovascularization were observed either. Efficacy was measured as a significant postoperative improvement in terms of the eye complication grading scales. Anterior segment optical coherence tomography images revealed a more homogeneous and stable ocular surface, with complete scaffold degradation occurring within 3-12 weeks after surgery. CONCLUSIONS: Our findings suggest that the surgical application of this allogeneic anterior human corneal substitute is feasible and safe, showing partial efficacy in the restoration of the corneal surface.

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PURPOSE: Group B streptococcus (GBS) remains a leading cause of invasive disease, mainly sepsis and meningitis, in infants < 3 months of age and of mortality among neonates. This study, a major component of the European DEVANI project (Design of a Vaccine Against Neonatal Infections) describes clinical and important microbiological characteristics of neonatal GBS diseases. It quantifies the rate of antenatal screening and intrapartum antibiotic prophylaxis among cases and identifies risk factors associated with an adverse outcome. METHODS: Clinical and microbiological data from 153 invasive neonatal cases (82 early-onset [EOD], 71 late-onset disease [LOD] cases) were collected in eight European countries from mid-2008 to end-2010. RESULTS: Respiratory distress was the most frequent clinical sign at onset of EOD, while meningitis is found in > 30% of LOD. The study revealed that 59% of mothers of EOD cases had not received antenatal screening, whilst GBS was detected in 48.5% of screened cases. Meningitis was associated with an adverse outcome in LOD cases, while prematurity and the presence of cardiocirculatory symptoms were associated with an adverse outcome in EOD cases. Capsular-polysaccharide type III was the most frequent in both EOD and LOD cases with regional differences in the clonal complex distribution. CONCLUSIONS: Standardizing recommendations related to neonatal GBS disease and increasing compliance might improve clinical care and the prevention of GBS EOD. But even full adherence to antenatal screening would miss a relevant number of EOD cases, thus, the most promising prophylactic approach against GBS EOD and LOD would be a vaccine for maternal immunization.

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The transcription factor Zeb1 has been identified as a crucial player in Kras-dependent oncogenesis. In pancreatic ductal adenocarcinoma (PDAC), Zeb1 is highly expressed in myofibroblasts and correlates with poor prognosis. As Kras mutations are key drivers in PDAC, we aimed here to assess the necessity of Zeb1 for Kras-driven PDAC and to define the role of Zeb1-expressing myofibroblasts in PDAC development. Genetically engineered mice with conditional pancreatic KrasG12D and Trp53 mutations (KPC) were crossed with Zeb1 haploinsufficient mice (Z+/-). Extensive PDAC was prominent in all 20-week-old KPC;Z+/+ mice, whereas only low-grade precursor lesions were detected in age-matched KPC;Z+/- littermates, with PDAC developing eventually in KPC;Z+/- aged animals. Zeb1 expression in myofibroblasts occurred early in tumorigenesis and Zeb1 haploinsufficiency retarded native expansion of stromal myofibroblasts during precursor-to-cancer progression. Zeb1 downregulation in mPSC repressed their activated gene profile, impaired their migratory and proliferative activity, and attenuated their tumor-supporting features. Conditioned media from Z+/+ mouse-activated (myofibroblast-like) pancreatic stellate cells (mPSC) boosted Ras activity in pancreatic cancer cells carrying mutant Kras; this effect was not observed when using conditioned media from Z+/- mPSC, revealing a paracrinal cooperative axis between Zeb1-expressing PSC and oncogenic Kras-bearing tumor cells. We conclude that Zeb1-expressing stromal myofibroblasts enable a heterotypic collaboration with the Kras-fated epithelial compartment, thus supporting pancreatic malignancy.Significance: Zeb1 expression in stromal myofibroblasts supports PDAC development via collaboration with the epithelial compartment bearing oncogenic Kras mutations. Cancer Res; 78(10); 2624-37. ©2018 AACR.

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Streptococcus agalactiae, estreptococo del grupo B (EGB), es la mayor causa de morbi-mortalidad entre los neonatos y un patógeno importante entre los pacientes adultos inmunodeprimidos. A pesar de los avances en la prevención y tratamiento de la infección neonatal, fruto de la implantación de las recomendaciones nacionales e internacionales que en las últimas dos décadas se han desarrollado para ello, aún quedan pendientes mejoras para el control definitivo de la enfermedad. En este sentido, la vacunación frente a EGB podría ser una medida eficaz para la prevención de la infección en aquellos casos donde la profilaxis intraparto no es útil y en pacientes adultos con factores de riesgo de desarrollar infección invasiva por EGB. Esta revisión resume los esfuerzos llevados a cabo para controlar esta infección y aporta información sobre el estado actual de las vacunas frente a EGB empleando diferentes estrategias en su diseño (AU)

Streptococcus agalactiae, group B Streptococcus (SGB), is the most important cause of morbi-mortality among newborn population, and an important pathogen among immunossupressed adult patients. Despite the advances in the treatment and prevention of neonatal infections as a consequence of implementation of national and international recommendations for prevention of infection, there are still some improvements for the final control of the disease. In this sense, the vaccination against SGB could be an effective measure for the prevention of disease in those cases where intrapartum prophylaxis is not useful and in adult patients with risk factors for invasive infection due to SGB. This review summarizes the efforts made until now in order to establish the control of the infection, and brings some information on the current state-of-the art of vaccines against SGB, in which different strategies in their design have been used (AU)

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Group B streptococcus (GBS) is a leading cause of invasive neonatal infections and a significant pathogen in immunocompromised adults. Screening to detect GBS colonization in pregnant women determines the need for antibiotic prophylaxis in that pregnancy. Efficient determination of the GBS colonization status of pregnant women is crucial. Methods that maximize the probability of GBS recovery are needed. The availability of technologies such as matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), molecular techniques, and chromogenic culture media, including Granada-type media, have changed the scenario for GBS detection and identification. This review presents and evaluates novel diagnostic tools, as well as classic identification techniques, for GBS species determination.

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Astrocytes actively participate in neuro-inflammatory processes associated to Alzheimer's disease (AD), and other brain pathologies. We recently showed that an astrocyte-specific intracellular signaling pathway involving an interaction of the phosphatase calcineurin with the transcription factor FOXO3 is a major driver in AD-associated pathological inflammation, suggesting a potential new druggable target for this devastating disease. We have now developed decoy molecules to interfere with calcineurin/FOXO3 interactions, and tested them in astrocytes and neuronal co-cultures exposed to amyloid-ß (Aß) toxicity. We observed that interference of calcineurin/FOXO3 interactions exerts a protective action against Aß-induced neuronal death and favors the production of a set of growth factors that we hypothesize form part of a cytoprotective pathway to resolve inflammation. Furthermore, interference of the Aß-induced interaction of calcineurin with FOXO3 by decoy compounds significantly decreased amyloid-ß protein precursor (AßPP) synthesis, reduced the AßPP amyloidogenic pathway, resulting in lower Aß levels, and blocked the expression of pro-inflammatory cytokines TNFα and IL-6 in astrocytes. Collectively, these data indicate that interrupting pro-inflammatory calcineurin/FOXO3 interactions in astrocytes triggered by Aß accumulation in brain may constitute an effective new therapeutic approach in AD. Future studies with intranasal delivery, or brain barrier permeable decoy compounds, are warranted.

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PURPOSE: Streptococcus agalactiae (Group B streptococcus, GBS) is increasingly recognized as a pathogen in adult populations, including the elderly. Appropriate treatment involves antibiotics. An alternative to this strategy would be the administration of a polysaccharide vaccine therefore the capsular serotypes and molecular characterization of circulating strains needs to be known. Few studies have been conducted in this population. METHODS: One hundred and seven GBS isolates collected from vagino-rectal swabs from 600 post-menopausal women were analysed for their capsular type, antimicrobial resistance and genetic relatedness (multilocus sequence typing, MLST). RESULTS: The colonization rate was 17.8%. Capsular type III was predominant (34.6%), followed by type V (22.4%). The most frequent sequence type (ST) was 19 (23.3%), followed by 23 (18.7%), 1 (16.8%) and 17 (12.1%). Isolates were assembled into three phylogenetic groups from ST-19, ST-23 and ST-17 founders. All isolates were susceptible to penicillin, whereas resistance to erythromycin and clindamycin was recorded in 23.4% and 20.6% of isolates, respectively. CONCLUSIONS: In our setting, the GBS colonization rate in postmenopausal women is similar to that reported in others populations studied. The population structure of these isolates is highly diverse and contains different STs. These data can contribute to the future development of a polysaccharide vaccine for preventing GBS infection in older adults.

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The haemolysin of Group B streptococci (GBS), a leading cause of neonatal infections, is a key virulence factor that has been implicated in the development of invasive infection. The frequency of non-haemolytic (NH) GBS isolates is around 5% among GBS carriers. To determine if similar rates are observed among invasive strains, we evaluated the incidence of NH strains among 199 GBS strains isolated from neonatal blood cultures (first week of life). Overall, we found two (1%) NH strains. This finding suggests that the frequency of NH GBS strains causing early onset invasive neonatal infection is lower than the reported frequency of NH GBS among colonizing strains.

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INTRODUCCIÓN: Las actuales medidas de prevención frente a la enfermedad neonatal causada por Streptococcus agalactiae, estreptococo del grupoB (EGB), son la realización de un cribado prenatal y la administración de profilaxis antibiótica intraparto con antimicrobianos adecuados. Una alternativa a esta estrategia sería la administración de una vacuna polisacarídica, por lo que es necesario conocer la distribución de serotipos capsulares de las cepas circulantes. MÉTODOS: Se estudiaron 188 cepas procedentes de gestantes del área sanitaria norte de Granada portadoras vaginorrectales de EGB y 24 de recién nacidos con enfermedad neonatal enviadas al laboratorio desde distintos hospitales andaluces. Se realizó antibiograma frente a penicilina, eritromicina y clindamicina siguiendo las normas del Clinical and Laboratory Standards Institute (CLSI), y se determinó su serotipo capsular mediante 2 métodos: aglutinación con partículas de látex y métodos moleculares. RESULTADOS: De las 188 cepas de S.agalactiae pertenecientes a mujeres embarazadas, se obtuvo una concordancia en los resultados del 80,8% entre ambas técnicas. Se detectó resistencia a eritromicina y clindamicina en el 16,5 y el 10,1% de cepas, respectivamente. En las cepas neonatales, en el 95,8% de los aislados los resultados obtenidos por ambas técnicas fueron coincidentes. Las tasas de resistencia frente a eritromicina y clindamicina fueron del 8,3 y del 4,1%, respectivamente. En ambos grupos de aislados el serotipo más frecuente fue el III y el más relacionado con resistencia frente a antimicrobianos, el V. CONCLUSIÓN: Se deberían realizar más estudios epidemiológicos que permitan continuar con una vigilancia de los serotipos causantes de enfermedad invasiva así como sus patrones de sensibilidad antibiótica utilizando métodos sensibles y específicos

INTRODUCTION: Current preventive measures against neonatal disease caused by Streptococcus agalactiae (GBS) are prenatal screening and intrapartum antibiotic prophylaxis with appropriate antimicrobials. An alternative to this strategy would be the administration of a polysaccharide vaccine as the distribution of capsular serotypes of circulating strains needs to be known. METHODS: A study was made of 188 strains from pregnant women carrying GBS and 24 newborns with neonatal disease. Susceptibility testing was performed with penicillin, erythromycin and clindamycin following CLSI standards, and capsular serotype was determined by two methods: latex agglutination and PCR. RESULTS: Of the 188 strains of S.agalactiae from the pregnant women, there was 80.8% agreement in the results between the two techniques. Resistant to erythromycin and clindamycin was found in 16.5% and 10.1%, respectively. For neonatal strains, 95.8% of the results obtained by the two techniques were identical. The rates of resistance to erythromycin and clindamycin were 8.3% and 4.1%, respectively. In both groups, most frequently isolated serotype was III, and the most related to antimicrobial resistance serotype was V. CONCLUSIÓN: Epidemiological studies are necessary to continue surveillance of serotypes causing invasive disease and its antibiotic sensitivity patterns using sensitive and specific methods

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INTRODUCTION: Current preventive measures against neonatal disease caused by Streptococcus agalactiae (GBS) are prenatal screening and intrapartum antibiotic prophylaxis with appropriate antimicrobials. An alternative to this strategy would be the administration of a polysaccharide vaccine as the distribution of capsular serotypes of circulating strains needs to be known. METHODS: A study was made of 188 strains from pregnant women carrying GBS and 24 newborns with neonatal disease. Susceptibility testing was performed with penicillin, erythromycin and clindamycin following CLSI standards, and capsular serotype was determined by two methods: latex agglutination and PCR. RESULTS: Of the 188 strains of S.agalactiae from the pregnant women, there was 80.8% agreement in the results between the two techniques. Resistant to erythromycin and clindamycin was found in 16.5% and 10.1%, respectively. For neonatal strains, 95.8% of the results obtained by the two techniques were identical. The rates of resistance to erythromycin and clindamycin were 8.3% and 4.1%, respectively. In both groups, most frequently isolated serotype was iii, and the most related to antimicrobial resistance serotype was v. CONCLUSION: Epidemiological studies are necessary to continue surveillance of serotypes causing invasive disease and its antibiotic sensitivity patterns using sensitive and specific methods.

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Group B streptococcus [(GBS or Streptococcus agalactiae)] is a leading cause of neonatal meningitis and septicaemia. Most clinical isolates express simultaneously a ß-haemolysin/cytolysin and a red polyenic pigment, two phenotypic traits important for GBS identification in medical microbiology. The genetic determinants encoding the GBS haemolysin and pigment have been elucidated and the molecular structure of the pigment has been determined. The cyl operon involved in haemolysin and pigment production is regulated by the major two-component system CovS/R, which coordinates the expression of multiple virulence factors of GBS. Genetic analyses indicated strongly that the haemolysin activity was due to a cytolytic toxin encoded by cylE. However, the biochemical nature of the GBS haemolysin has remained elusive for almost a century because of its instability during purification procedures. Recently, it has been suggested that the haemolytic and cytolytic activity of GBS is due to the ornithine rhamnopolyenic pigment and not to the CylE protein. Here we review and summarize our current knowledge of the genetics, regulation and biochemistry of these twin GBS phenotypic traits, including their functions as GBS virulence factors.

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AIM: To assess the prevalence and prognostic power of disseminated tumor cells (DTC) in patients with locally advanced breast cancer (LABC) before primary systemic therapy (PST). MATERIALS AND METHODS: LABC patients attending our Breast Unit were studied between 2002 and 2012, all of them being considered for PST. To determine the presence of DTC, posterior iliac crest aspirates were obtained and marrow samples were processed by gradient separation with Ficoll (Lymphoprep(®)) and immunohistochemical staining using the antiCK A45-B/B3 (EPIMET) antibody. Clinicopathologic variables were recorded before and after PST to assess response. Disease-free survival (DFS) and overall survival (OS) were determined after follow-up. The presence of DTC as a predictor of response to PST and as a prognostic tool for OS and DSF was evaluated. RESULTS: DTC were observed in 26% of 47 patients included in the study. PST consisted of chemotherapy in 94% and hormone therapy in 6%. Breast-conserving therapy was attained in 33%. Mean follow-up was 68 months. Complete clinical response (CR) after PST was seen in 26%, disease recurrence in 38%, and cancer-related death in 8%; tumor size and negative estrogen receptors were significant predictors of CR and mastectomy was associated with DFS. Persistent axillary disease after PST and previous recurrence were predictive of OS. DTC were detected more often in patients who did not achieve CR and those who presented recurrence. DTC detection was a significant prognostic factor for a worse OS (OR = 7.62; CI95%: 1.46-39.61; p = 0.009) and a decreased survival time (62 versus 82 months, p = 0.004). CONCLUSION: Presence of DTC before PST was found in a significant number of patients with LABC. DTC were found to be a significant prognostic factor for cancer-related death. DTC could be a surrogate predictor of response to PST and also of disease recurrence in LABC patients.

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La infección por Streptococcus agalactiae, estreptococo grupo B (EGB), continúa siendo la causa más frecuente de sepsis neonatal de etiología bacteriana. En 2003, las Sociedades Españolas de Ginecología y Obstetricia, Neonatología, Enfermedades Infecciosas y Microbiología Clínica, Quimioterapia y Medicina Familiar y Comunitaria publicaron recomendaciones actualizadas para la prevención de la infección neonatal precoz por EGB. En ellas se recomendaba la identificación de gestantes portadoras de EGB mediante cultivo de muestra de exudado vaginorrectal realizado en las 35-37 semanas de gestación y la administración de profilaxis antibiótica intraparto (PAI) a todas las gestantes colonizadas. En estas nuevas recomendaciones se actualizan los métodos microbiológicos para realizar la identificación de portadoras de EGB y la técnica de sensibilidad a antibióticos; se revisan los antibióticos de primera línea que pueden usarse para PAI (penicilina, ampicilina, cefazolina) y sus alternativas (clindamicina y vancomicina); se clarifica el significado de la presencia de EGB en orina, incluyendo criterios para el diagnóstico de infección urinaria y bacteriuria asintomática por EGB en la embarazada; se define el uso de PAI en la amenaza de parto prematuro y rotura prematura de membranas, y se revisa el manejo del recién nacido en relación con el estado de portadora de EGB de la madre. Estas recomendaciones solo son válidas para la prevención de la infección neonatal precoz por EGB, y no son efectivas frente a la infección neonatal tardía. Tras la aplicación generalizada de la PAI, la incidencia de la sepsis neonatal precoz por EGB ha disminuido (..) (AU)

Group B streptococci (GBS) remain the most common cause of early onset neonatal sepsis. In 2003 the Spanish Societies of Obstetrics and Gynaecology, Neonatology, Infectious Diseases and Clinical Microbiology, Chemotherapy, and Family and Community Medicine published updated recommendations for the prevention of early onset neonatal GBS infection. It was recommended to study all pregnant women at 35-37 weeks gestation to determine whether they were colonised by GBS, and to administer intrapartum antibiotic prophylaxis (IAP) to all colonised women. There has been a significant reduction in neonatal GBS infection in Spain following the widespread application of IAP. Today most cases of early onset GBS neonatal infection are due to false negative results in detecting GBS, to the lack of communication between laboratories and obstetric units, and to failures in implementing the prevention protocol. In 2010, new recommendations were published by the CDC, and this fact, together with the new knowledge and experience available, has led to the publishing of these new recommendations. The main changes in these revised recommendations include: microbiological methods to identify pregnant GBS carriers and for testing GBS antibiotic sensitivity, and the antibiotics used for IAP are updated; The significance of the presence of GBS in urine, including (..) (AU)

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Group B streptococci (GBS) remain the most common cause of early onset neonatal sepsis. In 2003 the Spanish Societies of Obstetrics and Gynaecology, Neonatology, Infectious Diseases and Clinical Microbiology, Chemotherapy, and Family and Community Medicine published updated recommendations for the prevention of early onset neonatal GBS infection. It was recommended to study all pregnant women at 35-37 weeks gestation to determine whether they were colonised by GBS, and to administer intrapartum antibiotic prophylaxis (IAP) to all colonised women. There has been a significant reduction in neonatal GBS infection in Spain following the widespread application of IAP. Today most cases of early onset GBS neonatal infection are due to false negative results in detecting GBS, to the lack of communication between laboratories and obstetric units, and to failures in implementing the prevention protocol. In 2010, new recommendations were published by the CDC, and this fact, together with the new knowledge and experience available, has led to the publishing of these new recommendations. The main changes in these revised recommendations include: microbiological methods to identify pregnant GBS carriers and for testing GBS antibiotic sensitivity, and the antibiotics used for IAP are updated; The significance of the presence of GBS in urine, including criteria for the diagnosis of UTI and asymptomatic bacteriuria in pregnancy are clarified; IAP in preterm labour and premature rupture of membranes, and the management of the newborn in relation to GBS carrier status of the mother are also revised. These recommendations are only addressed to the prevention of GBS early neonatal infection, are not effective against late neonatal infection.

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BACKGROUND: It has been suggested that selective sentinel node (SN) biopsy alone can be used to manage early breast cancer, but definite evidence to support this notion is lacking. The aim of this study was to investigate whether refraining from completion axillary lymph node dissection (ALND) suffices to produce the same prognostic information and disease control as proceeding with completion ALND in early breast cancer patients showing micrometastasis at SN biopsy. METHODS: This prospective, randomized clinical trial included patients with newly diagnosed early-stage breast cancer (T<3.5 cm, clinical N0, M0) who underwent surgical excision as primary treatment. All had micrometastatic SN. Patients were randomly assigned to one of the two study arms: complete ALND (control arm) or clinical follow-up (experimental arm). Median follow-up was 5 years, recurrence was assessed, and the primary end point was disease-free survival. RESULTS: From a total sample of 247 patients, 14 withdrew, leaving 112 in the control arm and 121 in the experimental arm. In 15 control subjects (13%), completion ALND was positive, with a low tumor burden. Four patients experienced disease recurrence: 1 (1%) of 108 control subjects and 3 (2.5%) of 119 experimental patients. There were no differences in disease-free survival (p=0.325) between arms and no cancer-related deaths. CONCLUSIONS: Our results strongly suggest that in early breast cancer patients with SN micrometastasis, selective SN lymphadenectomy suffices to control locoregional and distant disease, with no significant effects on survival.

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