Late diagnosis and HIV infection in children attending a service of specialized care for pediatric AIDS in Brazil

Introduction: This study describes the frequency of late diagnosis and HIV among children attending a pediatric AIDS clinic. Methods: Cross-sectional study in children exposed to HIV from 2005-2008. A questionnaire was given that included questions on demographics and clinical information. Results: Two-hundred twenty-one (97.8%) children were exposed to HIV during pregnancy/childbirth. A total of 193 (87.3%) children had late enrolment in the service and late access to HIV serology. The frequency of HIV was 21.3% (95% confidence interval [CI] 15.9%-26.7%). Protective factors were earlier diagnosis [odds ratio (OR)=0.17 (0.08-0.37)] and receiving complete prophylaxis [OR=0.29 (0.09-0.97)]; being born by vaginal delivery was a risk factor [OR=4.45 (1.47-13.47)]. Conclusions: There was a high frequency of late diagnosis in this patient cohort. Earlier diagnosis is an important measure for controlling HIV among children.

Acute kidney injury in a tropical country: a cohort study of 253 patients in an infectious diseases intensive care unit

Introduction: Acute kidney injury (AKI) is a frequent and potentially fatal complication in infectious diseases. The aim of this study was to investigate the clinical aspects of AKI associated with infectious diseases and the factors associated with mortality. Methods: This retrospective study was conducted in patients with AKI who were admitted to the intensive care unit (ICU) of a tertiary infectious diseases hospital from January 2003 to January 2012. The major underlying diseases and clinical and laboratory findings were evaluated. Results: A total of 253 cases were included. The mean age was 46±16 years, and 72% of the patients were male. The main diseases were human immunodeficiency virus (HIV) infection, HIV/acquired immunodeficiency syndrome (AIDS) (30%), tuberculosis (12%), leptospirosis (11%) and dengue (4%). Dialysis was performed in 70 cases (27.6%). The patients were classified as risk (4.4%), injury (63.6%) or failure (32%). The time between AKI diagnosis and dialysis was 3.6±4.7 days. Oliguria was observed in 112 cases (45.7%). The Acute Physiology and Chronic Health Evaluation (APACHE) II scores were higher in patients with HIV/AIDS (57±20, p-value=0.01) and dengue (68±11, p-value=0.01). Death occurred in 159 cases (62.8%). Mortality was higher in patients with HIV/AIDS (76.6%, p-value=0.02). A multivariate analysis identified the following independent risk factors for death: oliguria, metabolic acidosis, sepsis, hypovolemia, the need for vasoactive drugs, the need for mechanical ventilation and the APACHE II score. Conclusions: AKI is a common complication in infectious diseases, with high mortality. Mortality was higher in patients with HIV/AIDS, most likely due to the severity of immunosuppression and opportunistic diseases.

A description of the Australian early psychosis intervention model and a proposal to establish a Pilot Early Intervention Program in Santa Cruz de la Sierra, Bolívia

RESUMO: Em 2011, a Associação Psiquiátrica Mundial lançou um programa de bolsas de investigação para psiquiatras em início de carreira a partir de países de renda baixa ou média-baixa, no âmbito deste programa, o autor foi selecionado para uma bolsa de pesquisa no Centre for Youth Mental Health/Orygen Youth Health Research Centre da Universidade de Melbourne. Orygen, é a principal organização de pesquisa e tradução do conhecimento do mundo com foco em problemas de saúde mental em pessoas jovens. O estágio foi baseado em Prevenção e Intervenção Precoce Psychosis Centre (EPPIC), que faz parte do Orygen. EPPIC fornece programa de tratamento abrangente e integrada, baseada na comunidade para o primeiro episódio de psicose. Esta dissertação descreve o modelo EPPIC, e seus componentes essenciais e fatores que são necessários para uma implementação de serviço direito. Além disso, uma proposta de criação de um programa-piloto de intervenção psicose precoce é discutido. Este programa inclui um programa de extensão inovadora que combina princípios comerciais sólidos, com metas sociais, a fim de combater especificamente a maior barreira para o tratamento da psicose precoce na Bolívia: o estigma da doença mental. Ao utilizar uma equipe de tratamento móvel, multidisciplinar, que enfatiza os papéis dos gerentes do caso treinados focada em fornecer indivíduo intensiva e apoio familiar no lar, este programa irá prestar cuidados culturalmente apropriados que irá alavancar contribuições de um suprimento limitado de psiquiatras e mudar longe da dependência um sistema médico fragmentado. ---------------------------- ABSTRACT: In 2011, the World Psychiatric Association launched a programme of research fellowships for early-career psychiatrists from low- or lower-middle income countries, within this programme, the author was selected to a research fellowship at the Centre for Youth Mental Health/Orygen Youth Health Research Centre at University of Melbourne. Orygen, is the world’s leading research and knowledge translation organization focusing on mental ill-health in young people. The traineeship was based on Early Psychosis Prevention and Intervention Centre (EPPIC), which is part of Orygen. EPPIC provides comprehensive, integrated, community-based treatment program for first-episode psychosis. This dissertation describes the EPPIC model, and its core components and factors which are necessary to a right service implementation. Additionally, a proposal to establish a pilot early psychosis intervention programme is discussed. This programme includes an innovative outreach programme that combines sound business principals with social goals in order to specifically target the largest barrier to early psychosis treatment in Bolivia: the stigma of mental illness. By utilizing a mobile, multidisciplinary treatment team that emphasizes the roles of trained case managers focused on providing intensive individual and family support in the home, this programme will provide culturally appropriate care that will leverage contributions from a limited supply of psychiatrists and shift dependence away from a fragmented medical system.

Nosocomial infections in a neonatal intensive care unit during 16 years: 1997-2012

Introduction Surveillance of nosocomial infections (NIs) is an essential part of quality patient care; however, there are few reports of National Healthcare Safety Network (NHSN) surveillance in neonatal intensive care units (NICUs) and none in developing countries. The purpose of this study was to report the incidence of NIs, causative organisms, and antimicrobial susceptibility patterns in a large cohort of neonates admitted to the NICU during a 16-year period. Methods The patients were followed 5 times per week from birth to discharge or death, and epidemiological surveillance was conducted according to the NHSN. Results From January 1997 to December 2012, 4,615 neonates, representing 62,412 patient-days, were admitted to the NICU. The device-associated infection rates were as follows: 17.3 primary bloodstream infections per 1,000 central line-days and 3.2 pneumonia infections per 1,000 ventilator-days. A total of 1,182 microorganisms were isolated from sterile body site cultures in 902 neonates. Coagulase-negative staphylococci (CoNS) (34.3%) and Staphylococcus aureus (15.6%) were the most common etiologic agents isolated from cultures. The incidences of oxacillin-resistant CoNS and Staphylococcus aureus were 86.4% and 28.3%, respectively. Conclusions The most important NI remains bloodstream infection with staphylococci as the predominant pathogens, observed at much higher rates than those reported in the literature. Multiresistant microorganisms, especially oxacillin-resistant staphylococci and gram-negative bacilli resistant to cephalosporin were frequently found. Furthermore, by promoting strict hygiene measures and meticulous care of the infected infants, the process itself of evaluating the causative organisms was valuable.

Illness perception, knowledge and self-care about cervical cancer

Prevention plays a central role in early detection of cervical cancer. Common Sense Model proposes that the nature and organization of illness representations can guide actions related to health and how self-care is exercised. The aim of this study was to describe and compare illness perception, knowledge and self-care in women with and without cancer precursor lesions. Participants were 92 women (aged 18-59) from primary care unity divided into two groups: women with and without premalignant lesion. Measures for illness perception, knowledge and self-care were used. There was no statistically signifi cant difference (t test e chi-square test) between groups in the variables analyzed. Despite the risk for cervical cancer, women with precursor lesions do not adjust their illness perceptions, knowledge and self-care to the situation. These data show the need to warn women against the cervical cancer risks, because their distorted perceptions and lack of knowledge about the disease may hamper the screening and control of cervical cancer.

Evaluation of the predictive indices for candidemia in an adult intensive care unit

INTRODUCTION: To evaluate predictive indices for candidemia in an adult intensive care unit (ICU) and to propose a new index. METHODS: A prospective cohort study was conducted between January 2011 and December 2012. This study was performed in an ICU in a tertiary care hospital at a public university and included 114 patients staying in the adult ICU for at least 48 hours. The association of patient variables with candidemia was analyzed. RESULTS: There were 18 (15.8%) proven cases of candidemia and 96 (84.2%) cases without candidemia. Univariate analysis revealed the following risk factors: parenteral nutrition, severe sepsis, surgical procedure, dialysis, pancreatitis, acute renal failure, and an APACHE II score higher than 20. For the Candida score index, the odds ratio was 8.50 (95% CI, 2.57 to 28.09); the sensitivity, specificity, positive predictive value, and negative predictive value were 0.78, 0.71, 0.33, and 0.94, respectively. With respect to the clinical predictor index, the odds ratio was 9.45 (95%CI, 2.06 to 43.39); the sensitivity, specificity, positive predictive value, and negative predictive value were 0.89, 0.54, 0.27, and 0.96, respectively. The proposed candidemia index cutoff was 8.5; the sensitivity, specificity, positive predictive value, and negative predictive value were 0.77, 0.70, 0.33, and 0.94, respectively. CONCLUSIONS: The Candida score and clinical predictor index excluded candidemia satisfactorily. The effectiveness of the candidemia index was comparable to that of the Candida score.

Opportunistic infections among individuals with HIV-1/AIDS in the highly active antiretroviral therapy era at a Quaternary Level Care Teaching Hospital

INTRODUCTION : In this study, clinical-laboratory and epidemiological characteristics are described for a group of 700 individuals with HIV (human immunodeficiency virus)/AIDS (acquired immunodeficiency syndrome) in the ART (antiretroviral therapy) era at a teaching hospital that provides a quaternary level of care, with an emphasis on opportunistic infections (OIs), co-infections and immune profile. METHODS : A retrospective cross-sectional study of AIDS cases was conducted from 1998 to 2008 by reviewing medical records from the Base Hospital/FUNFARME (Fundação Faculdade Regional de Medicina), São José do Rio Preto, São Paulo, Brazil. RESULTS: The individuals were 14 to 75 years of age, and 458 were males. Heterosexuals accounted for 31.1% of all patients. Eighty-three percent were on ART, and 33.8% of those presented difficulties with treatment adherence. OIs were analyzed from medical records, and Pneumocystis jiroveci pneumonia was the most prevalent, regardless of the LTCD4+ (TCD4+ Lymphocytes) levels. Individuals whose viral loads were ≥10,000 showed a 90% greater chance of neurotoxoplasmosis. For P. jiroveci pneumonia, neurotoxoplasmosis, esophageal candidiasis, pulmonary tuberculosis and neurocryptococcosis, the chances of infection were higher among patients with LTCD4+ levels below 200 cells/mm3. HIV/hepatitis C virus (HCV) and HIV/hepatitis B virus (HBV) co-infections were significantly associated with death. CONCLUSIONS : OIs remain frequent in the ART era even in populations where the access to medical care is considered satisfactory.

Estimating demand for primary health care services

Primary health services exist with the purpose of providing basic health care to every person at a cost they can afford. But is it fully available to everyone? The objective of this work project is to estimate the demand for primary health care services having into account that in some regions the citizens are not using as much health care as they would like due to supply side constraints. Using the number of consultations as proxy for demand, and applying an econometric tool called switching regression, the demand for primary health care services will be estimated.

Secular trends in Klebsiella pneumoniae isolated in a tertiary-care hospital: increasing prevalence and accelerated decline in antimicrobial susceptibility

Abstract: INTRODUCTION Klebsiella pneumoniae has become an increasingly important etiologic agent of nosocomial infections in recent years. This is mainly due to the expression of virulence factors and development of resistance to several antimicrobial drugs. METHODS This retrospective study examines data obtained from the microbiology laboratory of a Brazilian tertiary-care hospital. To assess temporal trends in prevalence and antimicrobial susceptibility, K. pneumoniae isolates were analyzed from 2000 to 2013. The relative frequencies of K. pneumoniae isolation were calculated among all Gram-negative bacilli isolated in each period analyzed. Susceptibility tests were performed using automated systems. RESULTS: From 2000-2006, K. pneumonia isolates comprised 10.7% of isolated Gram-negative bacilli (455/4260). From 2007-2013, this percentage was 18.1% (965/5331). Strictly considering isolates from bloodstream infections, the relative annual prevalence of K. pneumoniae increased from 14-17% to 27-32% during the same periods. A progressive decrease in K. pneumoniae susceptibility to all antimicrobial agents assessed was detected. Partial resistance was also observed to antimicrobial drugs that have been used more recently, such as colistin and tigecycline. CONCLUSIONS Our study indicates that K. pneumoniae has become a major pathogen among hospitalized patients and confirms its recent trend of increasing antimicrobial resistance.

Chemotherapy versus best supportive care in stage IV non-small cell lung cancer, non metastatic to the brain

Stage IV non-small cell lung cancer is a fatal disease, with a median survival of 14 months. Systemic chemotherapy is the most common approach. However the impact in overall survival and quality of life still a controversy. OBJECTIVES: To determine differences in overall survival and quality of life among patients with stage IV non-small cell lung cancer non-metastatic to the brain treated with best supportive care versus systemic chemotherapy. PATIENTS: From February 1990 through December 1995, 78 eligible patients were admitted with the diagnosis of stage IV non-small cell lung cancer . Patients were divided in 2 groups: Group A (n=31 -- treated with best supportive care ), and Group B (n=47 -- treated with systemic chemotherapy). RESULTS: The median survival time was 23 weeks (range 5 -- 153 weeks) in Group A and 55 weeks (range 7.4 -- 213 weeks) in Group B (p=0.0018). In both groups, the incidence of admission for IV antibiotics and need of blood transfusions were similar. Patients receiving systemic chemotherapy were also stratified into those receiving mytomycin, vinblastin, and cisplatinum, n=25 and those receiving other combination regimens (platinum derivatives associated with other drugs, n=22). Patients receiving mytomycin, vinblastin, and cisplatinum, n=25 had a higher incidence of febrile neutropenia and had their cycles delayed for longer periods of time than the other group. These patients also had a shorter median survival time (51 versus 66 weeks, p=0.005). CONCLUSION: In patients with stage IV non-small cell lung cancer, non-metastatic to the brain, chemotherapy significantly increases survival compared with best supportive care.

Pediatric cardiac postoperative care

The Heart Institute of the University of São Paulo, Medical School is a referral center for the treatment of congenital heart diseases of neonates and infants. In the recent years, the excellent surgical results obtained in our institution may be in part due to modern anesthetic care and to postoperative care based on well-structured protocols. The purpose of this article is to review unique aspects of neonate cardiovascular physiology, the impact of extracorporeal circulation on postoperative evolution, and the prescription for pharmacological support of acute cardiac dysfunction based on our cardiac unit protocols. The main causes of low cardiac output after surgical correction of heart congenital disease are reviewed, and methods of treatment and support are proposed as derived from the relevant literature and our protocols.

Characterization of newborns with nonimmune hydrops fetalis admitted to a neonatal intensive care unit

PURPOSE: To determine the incidence and characteristics of nonimmune hydrops fetalis in the newborn population. METHOD: A retrospective study of the period between 1996 and 2000, including all newborns with a prenatal or early neonatal diagnosis of nonimmune hydrops fetalis, based on clinical history, physical examination, and laboratory evaluation. The following were analyzed: prenatal follow-up, delivery type, gender, birth weight, gestational age, presence of perinatal asphyxia, nutritional classification, etiopathic diagnosis, length of hospital stay, mortality, and age at death. RESULTS: A total of 47 newborns with hydrops fetalis (0.42% of live births), 18 (38.3%) with the immune form and 29 (61.7%) with the nonimmune form, were selected for study. The incidence of nonimmune hydrops fetalis was 1 per 414 neonates. Data was obtained from 21 newborns, with the following characteristics: 19 (90.5%) were suspected from prenatal diagnosis, 18 (85.7%) were born by cesarean delivery, 15 (71.4%) were female, and 10 (47.6%) were asphyxiated. The average weight was 2665.9 g, and the average gestational age was 35 3/7 weeks; 14 (66.6%) were preterm; 18 (85.0 %) appropriate delivery time; and 3 (14.3%) were large for gestational age. The etiopathic diagnosis was determined for 62%, which included cardiovascular (19.0%), infectious (9.5%), placental (4.8%), hematologic (4.7%), genitourinary (4.8%), and tumoral causes (4.8%), and there was a combination of causes in 9.5%. The etiology was classified as idiopathic in 38%. The length of hospital stay was 26.6 ± 23.6 days, and the mortality rate was 52.4%. CONCLUSIONS: The establishment of a suitable etiopathic diagnosis associated with prenatal detection of nonimmune hydrops fetalis can be an important step in reducing the neonatal mortality rate from this condition.

Factors that determine the level of care children and adolescents experiencing mental disorders receive

RESUMO: Resumo Uma prestação de serviços de saúde mental para crianças e adolescentes (CAMHS) oportuna, eficaz e baseada na evidência pode evitar incapacidade a longo prazo. No entanto, estes serviços são criticamente sub-financiados em todo o mundo. É um imperativo garantir que este precioso recurso não seja desperdiçado. Os governos e outras partes interessadas relevantes na área da saúde mental precisam de conhecer o estado de saúde mental da população, quais os recursos disponíveis e como melhor utilizar os recursos disponíveis para orientar uma política e decisões efectivas sobre os níveis de serviços. Objetivo: O objetivo deste artigo é explorar o papel da acuidade, gravidade e complexidade na determinação dos cuidados em saúde mental especializados recebidos por crianças e adolescentes que sofrem perturbações mentais. Métodos: Este estudo é exploratório envolvendo uma revisão sistemática da literatura. Foi realizada uma pesquisa com palavras-chave utilizando bases de dados PsychINFO, EMBASE, PubMed e MEDLINE. A literatura cinzenta também foi investigada com um enfoque nas abordagens sistémicas, organizacionais e políticas para a organização e comissionamento de CAMHS. Foram selecionados apenas documentos escritos em Inglês. Três países, Bélgica, Reino Unido e Estados Unidos, todos eles com modelos muito diferentes de organização de CAMHS, foram revistos para investigar de que forma os conceitos de acuidade, gravidade e complexidade foram utilizados na sua concepção de serviços para determinar o nível da assistência prestada. Resultados: Nem a Bélgica, nem o modelo norte-americano de CAMHS organização de serviço parecem estar alinhados com os principais conceitos na determinação do nível de prestação de serviços. O sistema de serviços do Reino Unido de CAMHS está mais estreitamente alinhado com esses conceitos e tem uma alocação de recursos mais equilibrada entre o hospital e a comunidade. O seu ponto fraco está na falta de flexibilidade entre os níveis de serviço e na falta de apoio para com o sector dos cuidados de saúde primários. Conclusões: A variabilidade na alocação de recursos a diferentes níveis especializados de CAMHS (em regime de internamento, ambulatório, e na comunidade) e o modelo diferente de estrutura de serviços entre os países estudados indica uma inconsistência na forma como as crianças e adolescentes que apresentam aos CAMHS são referenciados para os cuidados que recebem. Isto põe em questão se as crianças e adolescentes com perturbações mentais estão a receber o nível e tipo de cuidados concordantes com as suas necessidades. A concepção e o comissionamento de sistemas de CAMHS levam-nos à discussão de uma série de princípios fundamentais que devem ser considerados. O sistema perfeito no entanto, ainda está para ser encontrado. -------------------------------- ABSTRACT: Provision of timely, effective, evidence based mental health services to children and adolescents can prevent long term impairment, but they are critically underfunded across the globe. There is an imperative to ensure this precious resource is not wasted. Governments and other relevant mental health stakeholders need to know the mental health status of the population, what resources are available and how best to use the resources available to guide effective policy and decisions about service levels. Aim: The aim of this paper is to explore the role of acuity, severity and complexity in determining the specialist mental health care that children and adolescents experiencing mental disorders receive. Methods: This study is exploratory involving a systematic scan of the literature. A key word search was conducted using databases PSYCHINFO, EMBASE, PUBMED and MEDLINE. Grey literature was also searched to focus on systemic, organisational and policy approaches to the organisation and commissioning of CAMHS. Only documents written in English were selected. Three countries Belgium, UK and the US all with very different models of service organisation for CAMHS were reviewed to investigate how well the concepts of acuity, severity and complexity were used to determine the level of care delivered in their service design. Findings: Neither the Belgium nor the US model of CAMHS service organisation appear to align with the key concepts driving intensity of level of service provision. The UK CAMHS service system most closely aligns with the concepts. It has a more balanced resource allocation between hospital and community. Its downfall is in its lack of flexibility between service levels and its lack of support for the primary care sector. Conclusions: The variability in resource allocation to different service levels (inpatient, outpatient, community) within specialist CAMHS and the differing model of service structure across countries indicates an inconsistency in how children and adolescents presenting to CAMHS are allocated to the care they receive. This puts into question whether children and adolescent with mental disorders are receiving a level and type of care commensurate with their needs. In commissioning and designing CAMHS systems a number of key principles that should be considered are discussed. The perfect system however, is yet to be found.

Clinical decisions in breast cancer, a heterogenous disease

RESUMO: Introdução: Tratamento do carcinoma da mama Este trabalho inicia-se com a história do tratamento do carcinoma da mama, desde os primeiros documentos que descrevem doentes com carcinoma da mama até 1950. Desde 1950 até 2000 o diagnóstico, risco e as modalidades terapêuticas usadas no tratamento das doentes são mais detalhadas com ênfase nas terapêuticas locais, regionais e sistémicas. Parte 1:Quem tratar com terapêutica sistémica adjuvante Capítulo 1: A classificação TNM não está morta no carcinoma da mama Tem sido dito que a classificação TNM não é adequada para usar como ferramenta de prognóstico e decisão terapêutica no carcinoma da mama, especialmente em doentes com carcinoma detectado através de rastreio, que tem geralmente menores dimensões. A razão desta classificação não ser adequada prendese com o facto de não estarem incluidos parâmetros biológicos na classificação TNM atual. Pusemos a hipótese de que numa população com alta percentagem de carcinoma da mama não detectado em exames de rastreio, com uma mediana de idade baixa e com alta percentagem de estadios II e III, o estadiamento clássico, pela classificação TNM, é mais descriminatório que as características biológicas na determinação do prognóstico. Para isto analisámos uma população de doentes com carcinoma da mama tratados consecutivamente na mesma instituição, durante 10 anos. Caracterizámos os fatores de prognóstico do estadiamento clássico incluídos na classificação TNM e as variantes biológicas, presentemente não incluídas na classificação TNM. Quantificámos a capacidade de cada um dos factores de prognóstico para para prever a sobrevivência. A população é de 1699 doentes com carcinoma da mama que foram tratádos com terapêutica sistémica adjuvante. Individualmente, cada um dos fatores de prognostico, clássicos ou biológicos, diferem significativamente entre doentes que sobrevivem e que não sobrevivem. Explicitamente, como previsto, doentes com tumores maiores, envolvimento dos gânglios axilares, estadios TNM mais avançados, que não expressam recetor de esrogéneo, com amplificação do gene Her2, triplos negativos ou de menor diferenciação têm menor sobrevida. Na análise multivariada, só os fatores de prognostico da classificação TNM, o grau histológico e a amplificação do gene Her2, esta última com menos significância estatistica são preditores independentes de sobrevivência. Capítulo 2: Em busca de novos factores de prognostico: Poder preditivo e mecanismo das alterações de centrossomas em carcinoma da mama Compilámos inúmeros grupos de experiências de genómica feitas em tumores primários de doentes com carcinoma da mama para as quais existe informação prognóstica. Estas experiências são feitas com o objectivo de descobrir novos factores de prognóstico. Reanalisámos os dados, repetindo a mesma pergunta: Quais são os genes com expressão diferencial estatisticamente significativa entre doentes que recaíram e doentes que não recaíram. Identificámos 65 genes nestas condições e o MKI67, o gene que codifica a proteina Ki67, estava nesse grupo. Identificámos vários genes que se sabe estarem envolvidos no processo de agregação de centrossomas. O gene que considerámos mais promissor foi a kinesina KiFC1, que já tinha sido identificada como regulador da agregação de centrossomas. Anomalias cetrossomais numéricas e estruturais têm sido observadas em neoplasias. Há dados correlacionando anolmalias centrossomais estruturais e e numéricas com o grau de malignidade e os eventos precoces da carcinogénese. Mas estas anomalias centrossomais têm um peso para a célula que deve adapatar-se ou entrará em apoptose. Os nossos resultados sugerem que existe um mecanismo adaptativo, a agregação de centrossomas, com impacto prognóstico negativo. O nosso objetivo foi quantificar o valor prognóstico das anomalias centrossomais no carcinoma da mama. Para isto usámos material de doentes dos quais sabemos a história natural. Avaliámos os genes de agregação de centrossomas, KIFC1 e TACC3, nas amostras tumorais arquivadas em parafina: primeiro com PCR (polymerase chain reaction) quantitativa e depois com imunohistoquímica (IHQ). Apenas a proteína KIFC1 foi discriminatória em IHQ, não se tendo conseguido otimizar o anticorpo da TACC3. Os níveis proteicos de KIFC1 correlacionam-se com mau prognóstico. Nas doentes que recaíram observámos, no tumor primário, maior abundância desta proteína com localização nuclear. Em seguida, demonstrámos que a agregação de centrossomas é um fenómeno que ocorre in vivo. Identificámos centrossomas agregados em amostras de tumores primários de doentes que recaíram. Tecnicamente usámos microscopia de fluorescência e IHQ contra proteínas centrossomais que avaliámos nos tumores primários arquivados em blocos de parafina. Observámos agregação de centrossomas num pequeno número de doentes que recaíram, não validámos, ainda, este fenótipo celular em larga escala. Parte 2: Como tratar com terapêutica sistémica os vários subtipos de carcinoma da mama Capítulo 3: Quantas doenças estão englobadas na definição carcinoma da mama triplo negativo? (revisão) O carcinoma da mama triplo negativo é um tumor que não expressa três proteínas: recetor de estrogénio, recetor de progesterona e o recetor do fator de crescimento epidermico tipo 2 (Her2). As doentes com estes tumores não são ainda tratadas com terapêutica dirigida, possivelmente porque esta definição negativa não tem ajudado. Sabemos apenas as alterações genéticas que estes tumores não têm, não as que eles têm. Talvez por esta razão, estes tumores são o subtipo mais agressivo de carcinoma da mama. No entanto, na prática clínica observamos que estas doentes não têm sempre mau prognóstico, além de que dados de histopatologia e epidemiologia sugerem que esta definição negativa não está a capturar um único subtipo de carcinoma da mama, mas vários. Avaliámos criticamente esta evidência, clínica, histopatológica, epidemiológica e molecular. Há evidência de heterogeneidade, mas não é claro quantos subtipos estão englobados nesta definição de carcinoma da mama triplo negativo. A resposta a esta pergunta, e a identificação do fundamento molecular desta heterogeneidade vai ajudar a melhor definir o prognóstico e eventualmente a definir novos alvos terapêuticos nesta população difícil. Capítulo 4: Terapêuica sistémica em carcinoma da mama triplo negativo (revisão) A quimioterapia é a única terapêutica sistémica disponível para as doentes com carcinoma da mama triplo negativo, ao contrário dos outros dois subtipo de carcinoma da mama que têm com a terapêutica antiestrogénica e anti Her2, importantes benefícios. Apesar de terem surgido várias opções terapêuticas para estes doentes nennhuma terapêutica dirigida foi validada pelos ensaios clínicos conduzidos, possivelmente porque a biologia deste carcinoma ainda não foi elucidada. Muitos ensaios demonstram que os tumores triplos negativos beneficiam com quimioterapia e que as mais altas taxas de resposta patológica completa à terapêutica neoadjuvante são observadas precisamente nestes tumors. A resposta patológica completa correlaciona-se com a sobrevivência. Estamos a estudar regimes adjuvantes específicos para doentes com estes tumors, mas, neste momento, regimes de terceira geração com taxanos e antraciclinas são os mais promissores. O papel de subgrupos de fármacos específicos, como os sais de platina, mantémse mal definido. Quanto às antraciclinas e taxanos, estes grupos não mostraram beneficio específico em carcinoma da mama triplo negativo quando comparado com os outros subtipos. Os próprios carcinomas da mama triplos negativos são heterogéneos e carcinomas da mama basais triplos negativos com elevada taxa de proliferação e carcinomas da mama triplos negativos surgidos em doentes com mutação germinal BRCA1 poderão ser mais sensíveis a sais de platino e menos sensíveis a taxanos. Como a definição molecular ainda não foi explicada a busca de terapêutica dirigida vai continuar. Capítulo 5: Ensaio randomizado de fase II do anticorpo monoclonal contra o recetor do fator de crescimento epidérmico tipo 1 combinado com cisplatino versus cisplatino em monoterapia em doentes com carcinoma da mama triplo negativo metastizado O recetor do fator de crescimento epidérmico tipo 1 está sobre expresso nos tumores das doentes com carcinoma da mama triplo negativo metastizado, um subtipo agressivo de carcinoma da mama. Este ensaio investigou a combinação de cetuximab e cisplatino versus cisplatino isolado em doentes deste tipo. Doentes em primeira ou segunda linha de terapêutica para doença metastizada foram randomizadas, num sistema de 2 para 1, para receber até 6 ciclos da combinação de cisplatino e cetuximab ou cisplatino isolado. Às doentes randomizadas para o braço de monoterapia podiamos, após progressão, acrescentar cetuximab ou tratá-las com cetuximab isolado. O objetivo primário foi a taxa de resposta global. Os objetivos secundários foram a sobrevivência livre de doença, a sobrevivência global e o perfil de segurança dos fármacos. A população em análise foram 115 doentes tratadas com a combinação e 58 doentes tratadas com cisplatino em monoterapia, 31 destas em quem se documentou progressão passaram a ser tratadas com um regime que incluía cetuximab, isolado ou em combinação. A taxa de resposta global foi de 20% no braço da combinaçao e de 10% no braço da monoterapia (odds ratio, 2.13). A sobrevivência livre de doença foi de 3.7 meses no braço da combinação e de 1.5 meses no braço em monoterapia (hazard ratio, 0.67). A sobrevivência global foi de 12.9 meses no braço da combinação versus 9.4 meses no braço de cisplatino. Conclui-se que, apesar de não ter sido alcançado o objectivo primário, acrescentar cetuximab, duplica a resposta e prolonga tanto a sobrevivência livre de doença como a sobrevivência global. Capítulo 6: Bloquear a angiogénese para tratar o carcinoma da mama (revisão) A angiogénese é uma característica que define a neoplasia, porque tumores com mais de 1mm precisam de formar novos vasos para poderem crescer. Desde que se descobriram as moléculas que orquestram esta transformação, que se têm procurado desenvolver e testar fármacos que interfiram com este processo. No carcinoma da mama o bevacizumab foi o primeiro fármaco aprovado pela FDA em primeira linha para tratar doença metastática. Depois foram estudados um grupo de inibidores de tirosina cinase associados aos recetores transmembranares envolvidos na angiogénese como o VEGFR, PDGFR, KIT, RET, BRAF e Flt3: sunitinib, sorafenib, pazopanib e axitinib Neste capítulo, analisaram-se e resumiram-se os dados dos ensaios clínicos das drogas anti-angiogénicas no tratamaneto do carcinoma da mama. Os ensaios de fase III do bevacizumab em carcinoma da mama mostraram uma redução na progressão de doença de 22 a 52% e aumento da sobrevivência livre de doença de 1.2 a 5.5 meses mas nunca foi demonstrado prolongamento de sobrevivência. Os ensaios de fase III em carcinoma da mama adjuvante com bevacizumab são dois e foram ambos negativos. O ensaio de fase III com o inibidor da tirosina cinase, sunitinib foi negativo, enquanto que os ensaios de fase II com os inibidores da tirosina cinase sorafenib e pazopanib melhoraram alguns indicadores de resposta e sobrevivência. A endostatina foi testada no contexto neoadjuvante com antraciclinas e melhorou a taxa de resposta, mas, mais ensaios são necessários para estabelecer este fármaco. A maioria dos ensaios clínicos dos agentes antiangiogénicos em carcinoma da mama reportaram aumento da taxa de resposta e de sobrevivência livre de doença mas nunca aumento da sobrevivência global quando comparado com quimioterapia isolada o que levou ao cepticismo a que assistimos atualmente em relação ao bloqueio da angiogénese. Ensaios clínicos selecionados em doentes específicas com objetivos translacionais relacionados com material biológico colhido, preferefencialmente em diferentes intervalos da terapêutica, serão cruciais para o bloqueio da angiogénese sobreviver como estratégia terapêutica em carcinoma da mama. Capítulo 7: A resposta à hipoxia medeia a resistência primária ao sunitinib em carcinoma da mama localmente avançado O sunitinib é um fármaco antiangiogénico que nunca foi avaliado isolado em doentes com carcinoma da mama não tratadas. O nosso objetivo foi caracaterizar a atividade do sunitinib isolado e em combinação com o docetaxel em carcinoma da mama não tratado, localmente avançado ou operável, mas de dimensão superior a 2 cm, para compreender os mecanismos de resposta. Doze doentes foram tratadas com duas semanas iniciais de sunitinib seguido de quatro ciclos de combinação de sunitinib e docetaxel. A resposta, a reistência e a toxicidade foram avaliadas de acordo com parametros clínicos, ressonância magnética nuclear, tomografia de emissão de positrões, histopatologia e perfis de expressão genómica. Detetámos resistência primária ao sunitinib na janela inicial de duas semanas, evidenciada em quatro doentes que não responderam. À data da cirurgia, cinco doentes tinham tumor viável na mama e axila, quatro tinahm tumor viável na mama e três foram retiradas do ensaio. Não houve respostas patológicas completas. A comparação dos perfis de expressão genómica entre os respondedores e os não respondedores, aos quinze dias iniciais, permitiu-nos identificar sobre expressão de VEGF e outras vias angiogénicas nos não respondedores. Especificamente, em tumores resistentes ao sunitinib isolado detectámos uma resposta transcricional à hipoxia caracterizada por sobre expressão de vários dos genes alvo do HIF1α. Neste ensaio de sunitinib isolado em doentes não tratadas com carcinoma da mama localmente avançado, encontrámos evidência molecular de resistência primária ao sunitinib possivelmente mediada por sobre expressão de genes que respondem à hipoxia. Parte 3: Quando parar a terapêutica sistémica às doentes com carcinoma da mama Capítulo 8: Agressividade terapêutica ns últimos três meses de vida num estudo retrospetivo dum centro único Incluímos todos os adultos que morreram com tumores sólidos na instituição em 2003 e foram tratados com quimioterapia para tratar neoplaias metastizadas. Colhemos dados detalhados relacionados com quimioterapia e toxicidade nos últimos três meses de vida a partir do processo clínico. Trezentas e dezanove doentes foram incluídos, a mediana de idade foi 61 anos. A mediana de sobrevivência de doença metastática foi de 11 meses. 66% (211) dos doentes foram tratados com QT nos últimos 3 meses de vida, 37% foram tratados com QT no úlimo mês de vida e 21% nas últimas duas semanas. Nos doentes que foram tratados com QT nos últimos três meses de vida, 50% começaram um novo regime terapêutico neste período e 14% começaram um novo regime no último mês. Identificámos como determinantes de tratamento com QT no fim de vida a idade jovem, o carcinoma da mama, do ovário e do pâncreas. Concluímos que administrámos QT no fim de vida frequentemente e iniciámos novos regimes terapêuticos no último mês de vida em 14% dos casos. Precisamos de aprofundar este trabalho para compreender se esta atitude agressiva resulta em melhor paliação de sintomas e qualidade de vida no fim de vida dos doentes com neoplasias disseminadas. Capítulo 9: O tratamento do carcinoma da mama no fim de vida está a mudar? Quisémos caracterizar a modificação da tendência no uso de QT e de estratégias paliativas no fim de vida das doentes com carcinoma da mama em diferentes instituições e em intervalos de tempo diferentes. Para isto selecionámos doentes que morreram de carcinoma da mama durante 6 anos, entre 2007 e 2012, num hospital geral e comparámos com as doentes que morreram de carcinoma da mama em 2003 num centro oncológico. Avaliámos um total de 232 doentes. O grupo mais recente tem 114 doentes e o grupo anterior tem 118 doentes. Usámos estatística descritiva para caracterizar QT no fim de vida e o uso de estratégias paliativas. Ambas as coortes são comparáveis em termos das características do carcinoma da mama. Observámos aumento do uso de estatégias paliativas: consulta da dor, consulta de cuidados paliativos e radioterapia paliativa no cuidado das doentes com carcinoma da mama metastizado. Evidenciámos aumento do número de mortes em serviços de cuidados paliativos. No entanto, a QT paliativa continua a ser prolongada até aos últimos meses de vida, embora tenhamos mostrado uma diminuição desta prática. Outros indicadores de agressividade como a admissão hospitalar também mostraram diminuição. Confirmámos a nossa hipótese de que há maior integração da medicina paliativa multidisciplinar e menos agressividade na terapêutica sistémica das doentes com carcinoma da mama nos últimos meses de vida. Chapter 10: Porque é que os nossos doentes são tratados com quimioterapia até ao fim da vida? (editorial) Este capítulo começa por dar o exmeplo duma jovem de 22 anos que viveu três meses após começar QT paliatva. Este caso epitomiza a futilidade terapêutica e é usado como ponto de partida para explorar as razões pelas quais administramos QT no fim de vida aos doentes quando é inútil, tóxica, logisticamente complexa e cara. Será que estamos a prescrever QT até tarde demais? Os oncologistas fazem previsões excessivamente otimistas e têm uma atitude pró terapêutica excessiva e são criticados por outros intervenientes nas instituições de saúde por isto. Crescentemente doentes, familiares, associações de doentes, definidores de políticas de saúde, jornalistas e a sociedade em geral afloram este tema mas tornam-se inconsistentes quando se trata dum doente próximo em que se modifica o discurso para que se façam terapêuticas sitémicas agressivas. Há uma crescente cultura de preservação da qualidade de vida, paliação, abordagem sintomática, referenciação a unidades de cuidados paliativos e outros temas do fim de vida dos doentes oncológicos terminais. Infelizmente, este tema tem ganhado momentum não porque os oncologistas estejam a refletir criticamente sobre a sua prática, mas porque os custos dos cuidados de saúde são crescentes e incomportáveis. Seja qual fôr o motivo, as razões que levam os oncologistas a administrar QT no fim de vida devem ser criticamente elucidadas. Mas há poucos dados para nos guiar nesta fase delicada da vida dos doentes e os que existem são por vezes irreconciliáveis, é uma revisão destes dados que foi feita neste capítulo. Conclusão: A abordagem do carcinoma da mama no futuro? Na conclusão, tenta-se olhar para o futuro e prever como será a tomada a cargo dum doente com carcioma da mama amanhã. Faz-se uma avaliação das várias àreas desde prevenção, rastreio, suscetibilidade genética e comportamental e terapêutica. Na terapêutica separa-se a terapêutica locoregional, sistémica adjuvante e da doença metastizada. Nos três últimos parágrafos a história duma mulher com um carcinoma localmente avançado que sobre expressa o recetor Her2, serve como ilustração de como devemos estar preparados para incorporar evolução, heterogeneidade e dinamismo no cuidado de doentes com carcinoma da mama. -------------------------------------------------------------------------------------------------- ABSTRACT: Introduction: Breast cancer care in the past This work starts with an overview of the treatment of breast cancer (BC). From the first reports of patients ill with BC until 1950. From 1950 until 2000, there is a more detailed account on how BC patients were treated with emphasis on the different modalities, local, regional and systemic treatments and their evolution. Part 1: Who to treat with adjuvant systemic therapy? Chapter 1: TNM is not dead in breast cancer It has been said that the current TNM staging system might not be suitable for predicting breast cancer (BC) outcomes and for making therapeutic decisions, especially for patients with screen detected BC which is smaller. The reason for this is also due to the non inclusion of tumor biology parameters in the current TNM system. We hypothesize that in a population where there is still a large abundance of non screen detected BC, with a low median age of incidence and abundance of high TNM staged lesions, biology is still second to classical staging in predicting prognosis. We analyzed a population of consecutive BC patients from a single institution during ten years. We characterized current established prognostic factors, classical staging variables included in the current TNM staging system and biological variables, currently not included in the TNM system. We quantified the capacity of individual prognostic factors to predict survival. We analyzed a population of 1699 consecutive BC patients. We found that individually both the TNM system prognostic factors and the biological prognostic factors are differing among BC survivors and dead patients in a statistically significant distribution. Explicitly, patients with larger tumors, positive nodes, higher stage lesions, ER negative, HER2 positive, TN or lower differentiation tumors show decreased survival. In the multivariate analysis we can conclude that in a population such as ours classical TNM staging variables, irrespective of tumor biological features, are still the most powerful outcome predictors. Chapter 2: Defining breast cancer prognosis: The predictive power and mechanism of centrosome alterations in breast cancer We performed a systematic analysis of the literature and compiled an extensive data set of gene expression data originated in primary tumours of BC patients with prognostic information. We analysed this data seeking for genes consistently up or down regulated in poor prognosis BC, i.e. that relapsed after initial treatment. In the course this bioinformatics analysis our lab identified 65 genes statistically significant across multiple datasets that can discriminate between relapsed and non-relapsed BC patients. Among the identified genes, we have detected genes such as MKI67, a marker of mitotic activity which is routinely used in the clinic. Unexpectedly, we also discovered several genes found to be involved in centrosome clustering, The most prominent of these is the kinesin KIFC1, also called HSET, and previously identified as regulator of centrosome clustering. Centrosome abnormalities (numerical, structural) have been observed in cancer. Indeed, compelling data has shown that cells from many cancers have multiple and abnormal centrosomes, that are either correlated with tumour malignancy or considered an early tumorigenesis event. However, extra centrosomes come at a cost and cells must be able to handle such abnormalities or otherwise die. Thus our results suggested a new mechanism of breast cancer progression with negative prognostic value. We aimed at quantifying the predictive power of centrosome clustering in BC clinical setting and at detecting this process in BC patient material. We validated the centrosome clustering genes KIFC1 and TACC3 in formalin fixed paraffin embedded (FFPE) BC patient material, using quantitative real-time PCR (RT-qPCR) technology. Our results indicate that the tested KIFC1 has a clear IHC signal (1) and that the protein expression patterns and levels correlate with prognosis, with relapsing patients having increased expression and nuclear localisation of this kinesin (2). Next we were able to show that centrosome clustering does occur in vivo. We identified centrosome amplification and clustering in breast cancer samples, and we established a fluorescence microscopy-based IHC approach by staining FFPE samples with centrosomal markers. Using this approach we have observed centrosome amplification and clustering in a small set of poor prognosis samples. By expanding the number of samples in which we have characterised the number of centrosomes, we were able to confirm our preliminary observation that centrosomes are clustered in relapsed BC. Part 2: How to treat breast cancer subtypes? Chapter 3: How many diseases is triple negative breast cancer? (review) Triple negative breast cancer is a subtype of breast cancer that does not express the estrogen receptor, the progesterone receptor and the epidermal growth factor receptor type 2 (Her2). These tumors are not yet treated with targeted therapies probably because no positive markers have been described to reliably classify them - they are described for what they are not. Perhaps for this reason, they are among the most aggressive of breast carcinomas, albeit with very heterogenous clinical behavior. The clinical observation that these patients do not carry a uniformly dismal prognosis, coupled with data coming from pathology and epidemiology, suggests that this negative definition is not capturing a single clinical entity, but several. We critically evaluate this evidence in this paper, reviewing clinical and epidemiological data, as well as molecular data. There is evidence for heterogeneity, but it is not clear how many diseases are grouped into triple negative breast cancer. Answering this question, and identifying the molecular basis of heterogeneity will help define prognosis and, eventually, the identification of new targeted therapies. Chapter 4: Systemic treatment for triple negative breast cancer (review) Chemotherapy remains the backbone of treatment for triple negative breast cancer (TNBC). Despite the appearance of new targeted and biologic agents there has been no targeted therapy validated for TNBC, possibly because the biology of TNBC has not been conclusively elucidated. Many studies have shown that TNBC derive significant benefit of chemotherapy in the neoadjuvant, adjuvant and metastatic treatment, possibly more benefit than other BC subtypes. Neoadjuvant chemotherapy studies have repeatedly shown higher response rates in TNBC than non-TNBC. Pathologic complete response has been shown to predict improved long term outcomes in BC. Although specific adjuvant regimens for TNBC are under study, third generation chemotherapy regimens utilizing dose dense or metronomic polychemotherapy are among the most effective tools presently available. The role of specific chemotherapy agents, namely platinum salts, in the treatment of TNBC remains undefined. Taxanes and anthracyclines are active in TNBC and remain important agents, but have not shown specific benefit over non-TNBC. TNBC is itself a heterogeneous group in which subgroups like basal like BC defined by higher proliferation and including those TNBC arising in BRCA1 mutation carriers may be more sensitive to platinum agents and relatively less sensitive to taxanes. The molecular characterization of TNBC is lacking and therefore the search for targeted therapy is still ongoing. Chapter 5: Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer Epidermal growth factor receptor is overexpressed in metastatic triple-negative breast cancers, an aggressive subtype of breast cancer. Our randomized phase II study investigated cisplatin with or without cetuximab in this setting. Patients who had received no more than one previous chemotherapy regimen were randomly assigned on a 2:1 schedule to receive no more than six cycles of cisplatin plus cetuximab or cisplatin alone. Patients receiving cisplatin alone could switch to cisplatin plus cetuximab or cetuximab alone on disease progression. The primary end point was overall response rate (ORR). Secondary end points studied included progressionfree survival (PFS), overall survival (OS), and safety profiles. The full analysis set comprised 115 patients receiving cisplatin plus cetuximab and 58 receiving cisplatin alone; 31 patients whose disease progressed on cisplatin alone switched to cetuximab-containing therapy. The ORR was 20% with cisplatin plus cetuximab and 10% with cisplatin alone (odds ratio, 2.13). Cisplatin plus cetuximab resulted in longer PFS compared with cisplatin alone (median, 3.7 v 1.5 months; hazard ratio, 0.67. Corresponding median OS was 12.9 versus 9.4 months. While the primary study end point was not met, adding cetuximab to cisplatin doubled the ORR and appeared to prolong PFS and OS, warranting further investigation in mTNBC. Chapter 6: Blocking angiogenesis to treat breast cancer (review) Angiogenesis is a hallmark of cancer because tumors larger than 1mm need new vessels to sustain their growth. Since the discovery of the molecular players of this process and some inhibitors, that angiogenesis became a promising therapeutic target. Bevacizumab was the first molecular-targeted antiangiogenic therapy approved by the FDA and is used as first-line therapy in metastatic breast cancer. A second class of approved inhibitors (sunitinib, sorafenib, pazopanib and axitinib) include oral small-molecule tyrosine kinase inhibitors that target vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and other kinases including KIT, Ret, BRAF and Flt-3, but none of these have gained approval to treat breast cancer. This review analyzes and summarizes data from clinical trials of anti-angiogenic agents in the treatment of BC. Phase III trials of bevacizumab in advanced BC have demonstrated a reduction in disease progression (22–52%), increased response rates and improvements in progression-free survival of 1.2 to 5.5 months, but no improvements in OS. Bevacizumab phase III trials in early BC have both been negative. Bevacizumab combined with chemotherapy is associated with more adverse events. Phase III trials of the tyrosine kinase inhibitor sunitinib were negative, while randomized phase II trials of sorafenib and pazopanib have improved some outcomes. Endostatin has been tested in neoadjuvant clinical trials in combination with anthracyclinebased chemotherapy in treatment-naive patients and has increased the clinical response rate, but more trials are needed to establish this drug. Most trials of anti-angiogenic agents in BC have reported improved RR and PFS but no increase in OS compared to chemotherapy alone, leading to skepticism towards blocking angiogenesis. Selected trials in selected BC populations with translational endpoints related to harvested tumor tissue and other biological material samples, preferentially at several timepoints, will be crucial if antiangiogenesis is to survive as a strategy to treat BC. Chapter 7: Does hypoxic response mediate primary resistance to sunitinib in untreated locally advanced breast cancer? The antiangiogenic drug sunitinib has never been evaluated as single agent in untreated BC patients. We aimed to characterize the activity of sunitinib, alone and with docetaxel, in untreated locally advanced or operable BC, and, to uncover the mechanisms of response. Twelve patients were treated with an upfront window of sunitinib followed by four cycles of sunitinib plus docetaxel. Response, resistance and toxicity were evaluated according to standard clinical parameters, magnetic resonance imaging, positron emission tomography, pathology characterization and gene expression profiling. We detected primary resistance to sunitinib upfront window in untreated BC, as evidenced by four non-responding patients. At surgery, five patients had viable disease in the breast and axilla, four had viable tumor cells in the breast alone and three were taken off study due to unacceptable toxicity and thus not evaluated. Early functional imaging was useful in predicting response. There were no pathologic complete responses (pCR). Comparison of gene expression profiling tumor data between early responders and non-responders allowed us to identify upregulation of VEGF and angiogenic pathways in non responders. Specifically, in tumors resistant to the single-agent sunitinib we detected a transcriptional response to hypoxia characterized by over-expression of several HIF1α target genes. In this report of single-agent sunitinib treatment of untreated localized BC patients, we found molecular evidence of primary resistance to sunitinib likely mediated by up-regulation of hypoxia responsive genes. Part 3: When to stop systemic treatment of breast cancer patients? Chapter 8: The aggressiveness of cancer care in the last three months of life: a retrospective single centre analysis. All adult patients with solid tumors who died in our hospital in 2003 and received chemotherapy for advanced cancer, were included. Detailed data concerning chemotherapy and toxicity, in the last three months of life, were collected from patientsʼ clinical charts. A total of 319 patients were included. Median age was 61 years. Median time from diagnosis of metastatic disease to death was 11 months. The proportion of patients who received chemotherapy in the last three months of life was 66% (n=211), in the last month 37% and in the last two weeks 21%. Among patients who received chemotherapy in the last three months of life, 50% started a new chemotherapy regimen in this period and 14% in the last month. There was an increased probability of receiving chemotherapy in the last three months of life in younger patients and in patients with breast, ovarian and pancreatic carcinomas. There was a large proportion of patients who received chemotherapy in the last three months of life, including initiation of a new regimen within the last 30 days. Thus, further study is needed to evaluate if such aggressive attitude results in better palliation of symptoms at the end of life. Chapter 9: Is breast cancer treatment in the end of life changing? We aimed to characterize the shifting trends in use of anti-cancer chemotherapy and palliative care approaches in the end of life of BC patients in different institutions and times. For this, we selected women that died of BC during six years, from 2007 to 2012, and were treated in a central acute care general hospital and compared it with the BC patients that died in 2003 and were treated in a large cancer center. We analyzed a total of 232 patients: the more recent group has 114 women and the older cohort has 118. We used descriptive statistics to characterize CT in the EoL and use of palliative care resources. Both populations were similar in terms of BC characteristics. We observed more palliative care resources, pain clinic, palliative care teams and palliative radiotherapy, involved in the care of MBC patients and a shift towards more deaths at hospices. Systemic anti cancer treatments continue to be prolonged until very late in patients’ lives, notwithstanding, we could show a decrease in the use of such treatments. Other indicators of aggressiveness, namely hospital admissions, also show a decrease. We confirmed our hypothesis that there is more integration of multidisciplinary palliative care and less aggressiveness in the treatment of metastatic cancer patients, specifically, use of palliative anti-cancer treatment and hospital admissions. Nonetheless, we use systemic therapy until too late with underutilization of palliative medicine. Chapter 10: Why do our patients get chemotherapy until the end of life? (editorial) The editorial starts with a clinical case of a 21 year old patient that lives three months after starting palliative chemotherapy for the first time, a case that illustrates therapeutic futility at the end of life. Why are we not ceasing chemotherapy when it is useless, toxic, logistically complex and expensive? Are we prescribing chemotherapy until too late in solid tumor patientsʼ lives? Medical oncologists have overly optimistic predictions and, excessive, treatment-prone attitude and they are criticized by other health care providers for this. Increasingly, patients, their families, advocacy groups, policy makers, journalists and society at large dwell on this topic, which is a perplexing conundrum, because sometimes they are the ones demanding not to stop aggressive systemic anticancer treatments, when it comes to their loved ones. There is a growing culture of awareness toward preserving quality of life, palliative care, symptom-directed care, hospice referral and end of life issues regarding terminal cancer patients. Sadly, this issue is gaining momentum, not because oncologists are questioning their practice but because health care costs are soaring. Whatever the motive, the reasons for administering chemotherapy at the end of life should be known. There are few and conflicting scientific data to guide treatments in this delicate setting and we review this evidence in this paper. Conclusion: What is the future of breast cancer care? This work ends with a view into the future of BC care. Looking into the different areas from prevention, screening, hereditary BC, local, regional and systemic treatments of adjuvant and metastatic patients. The last three paragraphs are a final comment where the story of a patient with Her2 positive locally advanced breast cancer is used as paradigm of evolution, heterogeneity and dynamism in the management of BC.