Associations of baroreflex sensitivity, heart rate variability, and initial orthostatic hypotension with prenatal and recent postnatal methylmercury exposure in the Seychelles Child Development Study at age 19 years.

BACKGROUND: A few studies have suggested an association between prenatal exposure to methylmercury and decreased heart rate variability (HRV) related to autonomic heart function, but no study has examined this association using baroreflex sensitivity (BRS). In this study we assessed the distribution of BRS and immediate orthostatic hypotension (IOH) in young Seychellois adults and their associations with exposure to prenatal and recent postnatal methylmercury. METHODS: Subjects in the Seychelles Child Development Study (SCDS) main cohort were evaluated at age 19 years. Non-invasive beat-to-beat blood pressure (BP) monitoring (Finapres, Ohmeda) was performed at rest and during active standing in 95 consecutive subjects. Recent postnatal mercury exposure was measured in subjects' hair at the age of 19 years and prenatal exposure in maternal hair grown during pregnancy. BRS was estimated by sequence analysis to identify spontaneous ascending and descending BP ramps. HRV was estimated by the following markers: PNN50 (relative numbers of normal-to-normal intervals which are shorter by more than 50 ms than the immediately following normal-to-normal intervals); rMSSD (root mean of the squared sum of successive interval differences); LF/HF (low frequency/high frequency component ratio); ratio of the mean expiratory/inspiratory RR intervals (EI ratio); and the ratio between the longest RR interval 30 s after active standing and the shortest RR interval at 15 s (Max30/Min15). IOH was estimated by the deepest BP fall within the first 15 s after active standing up. RESULTS: Prenatal MeHg exposures were similar in boys and girls (6.7��4.3, 6.7��3.8 ng/g) but recent postnatal mercury levels were higher in males than females (11.2��5.8 vs 7.9��4.3 ng/g, p=0.003). Markers of autonomic heart rate control were within the normal range (BRS: 24.8��7 ms/mm Hg, PNN50: 24.9��6.8%, rMSSD: 68��22, LF/HF: 0.61��0.28) in both sexes. After standing, 51.4% of subjects had a transient systolic BP drop>40 mm Hg, but only 5.3% reported dizziness or had syncope. Prenatal and recent postnatal MeHg levels, overall, were not associated with BRS, E/I ratio, PNN50, rMSSD, LF/HF ratio, Max30/Min15 ratio, and IOH. CONCLUSIONS: This study provides no support for the hypothesis that prenatal or recent postnatal MeHg exposure from fish consumption is associated with impaired autonomic heart rate control.

Relationship between dietary patterns and body mass index in Hispanic children ages 4--19 years of age

Background. In over 30 years, the prevalence of overweight for children and adolescents has increased across the United States (Barlow et al., 2007; Ogden, Flegal, Carroll, & Johnson, 2002). Childhood obesity is linked with adverse physiological and psychological issues in youth and affects ethnic/minority populations in disproportionate rates (Barlow et al., 2007; Butte et al., 2006; Butte, Cai, Cole, Wilson, Fisher, Zakeri, Ellis, & Comuzzie, 2007). More importantly, overweight in children and youth tends to track into adulthood (McNaughton, Ball, Mishra, & Crawford, 2008; Ogden et al., 2002). Childhood obesity affects body functions such as the cardiovascular, respiratory, gastrointestinal, and endocrine systems, including emotional health (Barlow et al., 2007, Ogden et al., 2002). Several dietary factors have been associated with the development of obesity in children; however, these factors have not been fully elucidated, especially in ethnic/minority children. In particular, few studies have been done to determine the effects of different meal patterns on the development of obesity in children. Purpose. The purpose of the study is to examine the relationships between daily proportions of energy consumed and energy derived from fat across breakfast, lunch, dinner, and snack, and obesity among Hispanic children and adolescents. Methods. A cross-sectional design was used to evaluate the relationship between dietary patterns and overweight status in Hispanic children and adolescents 4-19 years of age who participated in the Viva La Familia Study. The goal of the Viva La Familia Study was to evaluate genetic and environmental factors affecting childhood obesity and its co-morbidities in the Hispanic population (Butte et al., 2006, 2007). The study enrolled 1030 Hispanic children and adolescents from 319 families and examined factors related to increased body weight by focusing on a multilevel analysis of extensive sociodemographic, genetic, metabolic, and behavioral data. Baseline dietary intakes of the children were collected using 24-hour recalls, and body mass index was calculated from measured height and weight, and classified using the CDC standards. Dietary data were analyzed using a GEE population-averaged panel-data model with a cluster variable family identifier to include possible correlations within related data sets. A linear regression model was used to analyze associations of dietary patterns using possible covariates, and to examine the percentage of daily energy coming from breakfast, lunch, dinner, and snack while adjusting for age, sex, and BMI z-score. Random-effects logistic regression models were used to determine the relationship of the dietary variables with obesity status and to understand if the percent energy intake (%EI) derived from fat from all meals (breakfast, lunch, dinner, and snacks) affected obesity. Results. Older children (age 4-19 years) consumed a higher percent of energy at lunch and dinner and less percent energy from snacks compared to younger children. Age was significantly associated with percentage of total energy intake (%TEI) for lunch, as well as dinner, while no association was found by gender. Percent of energy consumed from dinner significantly differed by obesity status, with obese children consuming more energy at dinner (p = 0.03), but no associations were found between percent energy from fat and obesity across all meals. Conclusions. Information from this study can be used to develop interventions that target dietary intake patterns in obesity prevention programs for Hispanic children and adolescents. In particular, intervention programs for children should target dietary patterns with energy intake that is spread throughout the day and earlier in the day. These results indicate that a longitudinal study should be used to further explore the relationship of dietary patterns and BMI in this and other populations (Dubois et al., 2008; Rodriquez & Moreno, 2006; Thompson et al., 2005; Wilson et al., in review, 2008). ^

Comparative study of the in-hospital case-fatality rate of leptospirosis between pediatric and adult patients of different age groups

The main objective was to compare the in-hospital case-fatality rate of leptospirosis between pediatric (< 19 years) and adult (>19 years) patients, taking into account gender, renal function, duration of symptoms and jaundice. Medical records of 1016 patients were reviewed. Comparative analysis was restricted to 840 patients (100 pediatric, 740 adults) with recorded information on the variables included in the analysis. Among these patients 81.7% were male and 91.5% were icteric. The case-fatality rate of leptospirosis was 14.4%. The odds of death adjusted for gender, jaundice, duration of symptoms, serum urea and serum creatinine were almost four times higher for the adult than for the pediatric group (odds ratio (OR) = 3.94; 95% confidence interval = 1.19-13.03, p = 0.029). Among adults, increased age was also significantly and independently associated with increased risk of death (p < 0.01). Older patients were also more often treated by dialysis. In conclusion, the data suggest that the in-hospital case fatality rate of leptospirosis is higher for adults than for children and adolescents, even after taking into account the effects of several potential risk factors of death. Among adults, older age was also strongly and independently associated with higher risk of death.

Metastasis of renal cell carcinoma to the buccal mucosa 19 years after radical nephrectomy

Renal cell carcinoma (RCC) has high metastatic potential, which requires early diagnosis to optimize the chance of cure. Metastasis of RCC to the head and neck region is less common and metastasis to the buccal mucosa is extremely rare. This phenomenon occurs mostly in patients with generalized dissemination, especially with lung metastases. In this article we report a case of buccal mucosa metastasis from RCC in a 65-year-old man who presented 19 years after undergoing a left radical nephrectomy for clear cell RCC. Surgical excision of the buccal lesion was performed without evidence of recurrence or new metastatic lesions after 6 years of followup. To our knowledge, this is the first case of metastasis to the buccal mucosa from a RCC reported in the literature.

Complication and failure rates of tooth-supported fixed dental prostheses after 7 to 19 years in function

The aims of this study were to reexamine patients who had received fixed dental prostheses (FDPs) more than 10 years prior, list the frequencies of observed technical and biologic failures and complications, and calculate the estimated failure and complication rates at 10 and 15 years.

Tracking of fatness during childhood, adolescence and young adulthood: a 7-year follow-up study in Madeira Island, Portugal

Aims: Investigating tracking of fatness from childhood to adolescence, early adolescence to young adulthood and late adolescence to young adulthood. Subjects and methods: Participants from the Madeira Growth Study were followed during an average period of 7.2 years. Height, body mass, skin-folds and circumferences were measured, nine health- and performance-related tests were administered and the Baecke questionnaire was used to assess physical activity. Skeletal maturity was estimated using the TW3 method. Results: The prevalence of overweight plus obesity ranged from 8.2���20.0% at baseline and from 20.4���40.0% at followup, in boys. Corresponding percentages for girls were 10.6��� 12.0% and 13.2���18.0%. Inter-age correlations for fatness indicators ranged from 0.43���0.77. BMI, waist circumference and sum of skin-folds at 8, 12 and 16-years old were the main predictors of these variables at 15, 19 and 23-years old, respectively. Strength, muscular endurance and aerobic ���tness were negatively related to body fatness. Physical activity and maturation were independently associated with adolescent (15 years) and young adult (19 years) fatness. Conclusions: Over 7.2 years, tracking was moderate-to-high for fatness. Variance was explained by fatness indicators and to a small extent by physical ���tness, physical activity and maturation.

Tracking of fatness during childhood, adolescence and young adulthood: a 7-year follow-up study in Madeira Island, Portugal

Aims: Investigating tracking of fatness from childhood to adolescence, early adolescence to young adulthood and late adolescence to young adulthood. Subjects and methods: Participants from the Madeira Growth Study were followed during an average period of 7.2 years. Height, body mass, skin-folds and circumferences were measured, nine health- and performance-related tests were administered and the Baecke questionnaire was used to assess physical activity. Skeletal maturity was estimated using the TW3 method. Results: The prevalence of overweight plus obesity ranged from 8.2���20.0% at baseline and from 20.4���40.0% at followup, in boys. Corresponding percentages for girls were 10.6��� 12.0% and 13.2���18.0%. Inter-age correlations for fatness indicators ranged from 0.43���0.77. BMI, waist circumference and sum of skin-folds at 8, 12 and 16-years old were the main predictors of these variables at 15, 19 and 23-years old, respectively. Strength, muscular endurance and aerobic ���tness were negatively related to body fatness. Physical activity and maturation were independently associated with adolescent (15 years) and young adult (19 years) fatness. Conclusions: Over 7.2 years, tracking was moderate-to-high for fatness. Variance was explained by fatness indicators and to a small extent by physical ���tness, physical activity and maturation.

Immunogenicity of three recombinant hepatitis B vaccines administered to students in three doses containing half the antigen amount routinely used for adult vaccination

We evaluated the immunogenicity of three recombinant hepatitis B vaccines, one Brazilian (Butang, Instituto Butantan) and two Korean vaccines (Euvax-B, LG Chemical Ltd. and Hepavax-Gene, Greencross Vaccine Corp.), administered intramuscularly to students aged 17 to 19 years in three 10-��g doses (corresponding to half the amount of antigen routinely used for adult vaccination) at intervals of one month between the first and second dose, and of four months between the second and third dose. A total of 316 students non-reactive for any serological marker of hepatitis B virus infection were vaccinated: 77 (24.4%) with the Butang vaccine, 71 (22.5%) with Euvax-B, 85 (26.9%) with Hepavax-Gene and, for comparison, 83 (26.2%) with Engerix-B (GlaxoSmithKline), whose efficacy in young adults at the dose used here has been confirmed in previous studies. Similar seroconversion rates (anti-HBs > 10 mIU/mL about one month after application of the third dose) were obtained for the Butang, Euvax-B, Hepavax-Gene and Engerix-B vaccines (96.2%, 98.6%, 96.5% and 97.6%, respectively). The frequency of good responders (anti-HBs > 100 mIU/mL) was also similar among students receiving the four vaccines (85.8%, 91.6%, 89.4% and 89.2%, respectively). The geometric mean titers (GMT) of anti-HBs about one month after the third dose obtained with these vaccines were 727.78 �� 6.46 mIU/mL, 2009.09 �� 7.16 mIU/mL, 1729.82 �� 8.85 mIU/mL and 2070.14 �� 11.69 mIU/mL, respectively. The GMT of anti-HBs induced by the Euvax-B and Engerix-B vaccines were higher than those obtained with the Butang vaccine (p < 0.05); this difference was not significant when comparing the other vaccines two-by-two. No spontaneous adverse effects attributable to the application of any dose of the four vaccines were reported.

Encerramento Percut��neo de Shunts Interauriculares: Experi��ncia de uma D��cada de um Centro Terci��rio

INTRODUCTION: Atrial septal defects (ASD) are among the most common congenital anomalies and account for 10% of congenital heart disease in the pediatric age-group and 30% in adults. Closure is indicated when there is evidence of hemodynamic significance or after a paradoxical embolic event. Ten years ago, percutaneous closure became the treatment of choice in our center for all patients with a clear indication and favorable anatomy. In this paper we report the experience of this first decade. OBJECTIVE: To assess the short- and long-term results of our ten-year experience with percutaneous closure of atrial septal defects. METHODS: We studied retrospectively all patients with ASD treated with a percutaneous approach between November 1998 and December 2008. The pediatric age-group consisted of patients younger than 19 years old. Demographic data, clinical indications, minor and major complication rates, success rate and long-term outcome were assessed. RESULTS: In the first ten years of experience 510 patients, of whom 166 were in the pediatric group, were treated in our center by a team of adult and pediatric cardiologists. The overall success rate of the procedure was 98% (97.5% in ASD and 99.5% in patent foramen ovale (PFO). The minor complication rate was 3% (3.4% in ASD and 2% in PFO). The most frequent complication was supraventricular tachycardia. The major complication rate was 1.2% (0.6% in ASD and 2% in PFO). Two patients developed cardiac tamponade due to hemopericardium that was resolved by pericardiocentesis, without need for surgery. One patient had an arterial pseudoaneurysm corrected by vascular surgery. There was no device embolization and no need for urgent surgery in this population. During follow-up two patients had recurrence of ischemic stroke, one had a transient ischemic attack and another had a hemorrhagic stroke. Mortality was 0.6% (0.6% in ASD and 0.5% in PFO). There were no in-hospital deaths. During follow-up there were two deaths, both in the adult group. DISCUSSION AND CONCLUSION: In this population the success rate was high and most of the complications were minor. The results of this collaboration between adult and pediatric cardiologists in the first ten years of activity confirm the safety and efficacy of percutaneous closure of septal defects, when there is careful patient selection and a standardized technique.

Clinical decisions in breast cancer, a heterogenous disease

RESUMO: Introdu����o: Tratamento do carcinoma da mama Este trabalho inicia-se com a hist��ria do tratamento do carcinoma da mama, desde os primeiros documentos que descrevem doentes com carcinoma da mama at�� 1950. Desde 1950 at�� 2000 o diagn��stico, risco e as modalidades terap��uticas usadas no tratamento das doentes s��o mais detalhadas com ��nfase nas terap��uticas locais, regionais e sist��micas. Parte 1:Quem tratar com terap��utica sist��mica adjuvante Cap��tulo 1: A classifica����o TNM n��o est�� morta no carcinoma da mama Tem sido dito que a classifica����o TNM n��o �� adequada para usar como ferramenta de progn��stico e decis��o terap��utica no carcinoma da mama, especialmente em doentes com carcinoma detectado atrav��s de rastreio, que tem geralmente menores dimens��es. A raz��o desta classifica����o n��o ser adequada prendese com o facto de n��o estarem incluidos par��metros biol��gicos na classifica����o TNM atual. Pusemos a hip��tese de que numa popula����o com alta percentagem de carcinoma da mama n��o detectado em exames de rastreio, com uma mediana de idade baixa e com alta percentagem de estadios II e III, o estadiamento cl��ssico, pela classifica����o TNM, �� mais descriminat��rio que as caracter��sticas biol��gicas na determina����o do progn��stico. Para isto analis��mos uma popula����o de doentes com carcinoma da mama tratados consecutivamente na mesma institui����o, durante 10 anos. Caracteriz��mos os fatores de progn��stico do estadiamento cl��ssico inclu��dos na classifica����o TNM e as variantes biol��gicas, presentemente n��o inclu��das na classifica����o TNM. Quantific��mos a capacidade de cada um dos factores de progn��stico para para prever a sobreviv��ncia. A popula����o �� de 1699 doentes com carcinoma da mama que foram trat��dos com terap��utica sist��mica adjuvante. Individualmente, cada um dos fatores de prognostico, cl��ssicos ou biol��gicos, diferem significativamente entre doentes que sobrevivem e que n��o sobrevivem. Explicitamente, como previsto, doentes com tumores maiores, envolvimento dos g��nglios axilares, estadios TNM mais avan��ados, que n��o expressam recetor de esrog��neo, com amplifica����o do gene Her2, triplos negativos ou de menor diferencia����o t��m menor sobrevida. Na an��lise multivariada, s�� os fatores de prognostico da classifica����o TNM, o grau histol��gico e a amplifica����o do gene Her2, esta ��ltima com menos signific��ncia estatistica s��o preditores independentes de sobreviv��ncia. Cap��tulo 2: Em busca de novos factores de prognostico: Poder preditivo e mecanismo das altera����es de centrossomas em carcinoma da mama Compil��mos in��meros grupos de experi��ncias de gen��mica feitas em tumores prim��rios de doentes com carcinoma da mama para as quais existe informa����o progn��stica. Estas experi��ncias s��o feitas com o objectivo de descobrir novos factores de progn��stico. Reanalis��mos os dados, repetindo a mesma pergunta: Quais s��o os genes com express��o diferencial estatisticamente significativa entre doentes que reca��ram e doentes que n��o reca��ram. Identific��mos 65 genes nestas condi����es e o MKI67, o gene que codifica a proteina Ki67, estava nesse grupo. Identific��mos v��rios genes que se sabe estarem envolvidos no processo de agrega����o de centrossomas. O gene que consider��mos mais promissor foi a kinesina KiFC1, que j�� tinha sido identificada como regulador da agrega����o de centrossomas. Anomalias cetrossomais num��ricas e estruturais t��m sido observadas em neoplasias. H�� dados correlacionando anolmalias centrossomais estruturais e e num��ricas com o grau de malignidade e os eventos precoces da carcinog��nese. Mas estas anomalias centrossomais t��m um peso para a c��lula que deve adapatar-se ou entrar�� em apoptose. Os nossos resultados sugerem que existe um mecanismo adaptativo, a agrega����o de centrossomas, com impacto progn��stico negativo. O nosso objetivo foi quantificar o valor progn��stico das anomalias centrossomais no carcinoma da mama. Para isto us��mos material de doentes dos quais sabemos a hist��ria natural. Avali��mos os genes de agrega����o de centrossomas, KIFC1 e TACC3, nas amostras tumorais arquivadas em parafina: primeiro com PCR (polymerase chain reaction) quantitativa e depois com imunohistoqu��mica (IHQ). Apenas a prote��na KIFC1 foi discriminat��ria em IHQ, n��o se tendo conseguido otimizar o anticorpo da TACC3. Os n��veis proteicos de KIFC1 correlacionam-se com mau progn��stico. Nas doentes que reca��ram observ��mos, no tumor prim��rio, maior abund��ncia desta prote��na com localiza����o nuclear. Em seguida, demonstr��mos que a agrega����o de centrossomas �� um fen��meno que ocorre in vivo. Identific��mos centrossomas agregados em amostras de tumores prim��rios de doentes que reca��ram. Tecnicamente us��mos microscopia de fluoresc��ncia e IHQ contra prote��nas centrossomais que avali��mos nos tumores prim��rios arquivados em blocos de parafina. Observ��mos agrega����o de centrossomas num pequeno n��mero de doentes que reca��ram, n��o valid��mos, ainda, este fen��tipo celular em larga escala. Parte 2: Como tratar com terap��utica sist��mica os v��rios subtipos de carcinoma da mama Cap��tulo 3: Quantas doen��as est��o englobadas na defini����o carcinoma da mama triplo negativo? (revis��o) O carcinoma da mama triplo negativo �� um tumor que n��o expressa tr��s prote��nas: recetor de estrog��nio, recetor de progesterona e o recetor do fator de crescimento epidermico tipo 2 (Her2). As doentes com estes tumores n��o s��o ainda tratadas com terap��utica dirigida, possivelmente porque esta defini����o negativa n��o tem ajudado. Sabemos apenas as altera����es gen��ticas que estes tumores n��o t��m, n��o as que eles t��m. Talvez por esta raz��o, estes tumores s��o o subtipo mais agressivo de carcinoma da mama. No entanto, na pr��tica cl��nica observamos que estas doentes n��o t��m sempre mau progn��stico, al��m de que dados de histopatologia e epidemiologia sugerem que esta defini����o negativa n��o est�� a capturar um ��nico subtipo de carcinoma da mama, mas v��rios. Avali��mos criticamente esta evid��ncia, cl��nica, histopatol��gica, epidemiol��gica e molecular. H�� evid��ncia de heterogeneidade, mas n��o �� claro quantos subtipos est��o englobados nesta defini����o de carcinoma da mama triplo negativo. A resposta a esta pergunta, e a identifica����o do fundamento molecular desta heterogeneidade vai ajudar a melhor definir o progn��stico e eventualmente a definir novos alvos terap��uticos nesta popula����o dif��cil. Cap��tulo 4: Terap��uica sist��mica em carcinoma da mama triplo negativo (revis��o) A quimioterapia �� a ��nica terap��utica sist��mica dispon��vel para as doentes com carcinoma da mama triplo negativo, ao contr��rio dos outros dois subtipo de carcinoma da mama que t��m com a terap��utica antiestrog��nica e anti Her2, importantes benef��cios. Apesar de terem surgido v��rias op����es terap��uticas para estes doentes nennhuma terap��utica dirigida foi validada pelos ensaios cl��nicos conduzidos, possivelmente porque a biologia deste carcinoma ainda n��o foi elucidada. Muitos ensaios demonstram que os tumores triplos negativos beneficiam com quimioterapia e que as mais altas taxas de resposta patol��gica completa �� terap��utica neoadjuvante s��o observadas precisamente nestes tumors. A resposta patol��gica completa correlaciona-se com a sobreviv��ncia. Estamos a estudar regimes adjuvantes espec��ficos para doentes com estes tumors, mas, neste momento, regimes de terceira gera����o com taxanos e antraciclinas s��o os mais promissores. O papel de subgrupos de f��rmacos espec��ficos, como os sais de platina, mant��mse mal definido. Quanto ��s antraciclinas e taxanos, estes grupos n��o mostraram beneficio espec��fico em carcinoma da mama triplo negativo quando comparado com os outros subtipos. Os pr��prios carcinomas da mama triplos negativos s��o heterog��neos e carcinomas da mama basais triplos negativos com elevada taxa de prolifera����o e carcinomas da mama triplos negativos surgidos em doentes com muta����o germinal BRCA1 poder��o ser mais sens��veis a sais de platino e menos sens��veis a taxanos. Como a defini����o molecular ainda n��o foi explicada a busca de terap��utica dirigida vai continuar. Cap��tulo 5: Ensaio randomizado de fase II do anticorpo monoclonal contra o recetor do fator de crescimento epid��rmico tipo 1 combinado com cisplatino versus cisplatino em monoterapia em doentes com carcinoma da mama triplo negativo metastizado O recetor do fator de crescimento epid��rmico tipo 1 est�� sobre expresso nos tumores das doentes com carcinoma da mama triplo negativo metastizado, um subtipo agressivo de carcinoma da mama. Este ensaio investigou a combina����o de cetuximab e cisplatino versus cisplatino isolado em doentes deste tipo. Doentes em primeira ou segunda linha de terap��utica para doen��a metastizada foram randomizadas, num sistema de 2 para 1, para receber at�� 6 ciclos da combina����o de cisplatino e cetuximab ou cisplatino isolado. ��s doentes randomizadas para o bra��o de monoterapia podiamos, ap��s progress��o, acrescentar cetuximab ou trat��-las com cetuximab isolado. O objetivo prim��rio foi a taxa de resposta global. Os objetivos secund��rios foram a sobreviv��ncia livre de doen��a, a sobreviv��ncia global e o perfil de seguran��a dos f��rmacos. A popula����o em an��lise foram 115 doentes tratadas com a combina����o e 58 doentes tratadas com cisplatino em monoterapia, 31 destas em quem se documentou progress��o passaram a ser tratadas com um regime que inclu��a cetuximab, isolado ou em combina����o. A taxa de resposta global foi de 20% no bra��o da combina��ao e de 10% no bra��o da monoterapia (odds ratio, 2.13). A sobreviv��ncia livre de doen��a foi de 3.7 meses no bra��o da combina����o e de 1.5 meses no bra��o em monoterapia (hazard ratio, 0.67). A sobreviv��ncia global foi de 12.9 meses no bra��o da combina����o versus 9.4 meses no bra��o de cisplatino. Conclui-se que, apesar de n��o ter sido alcan��ado o objectivo prim��rio, acrescentar cetuximab, duplica a resposta e prolonga tanto a sobreviv��ncia livre de doen��a como a sobreviv��ncia global. Cap��tulo 6: Bloquear a angiog��nese para tratar o carcinoma da mama (revis��o) A angiog��nese �� uma caracter��stica que define a neoplasia, porque tumores com mais de 1mm precisam de formar novos vasos para poderem crescer. Desde que se descobriram as mol��culas que orquestram esta transforma����o, que se t��m procurado desenvolver e testar f��rmacos que interfiram com este processo. No carcinoma da mama o bevacizumab foi o primeiro f��rmaco aprovado pela FDA em primeira linha para tratar doen��a metast��tica. Depois foram estudados um grupo de inibidores de tirosina cinase associados aos recetores transmembranares envolvidos na angiog��nese como o VEGFR, PDGFR, KIT, RET, BRAF e Flt3: sunitinib, sorafenib, pazopanib e axitinib Neste cap��tulo, analisaram-se e resumiram-se os dados dos ensaios cl��nicos das drogas anti-angiog��nicas no tratamaneto do carcinoma da mama. Os ensaios de fase III do bevacizumab em carcinoma da mama mostraram uma redu����o na progress��o de doen��a de 22 a 52% e aumento da sobreviv��ncia livre de doen��a de 1.2 a 5.5 meses mas nunca foi demonstrado prolongamento de sobreviv��ncia. Os ensaios de fase III em carcinoma da mama adjuvante com bevacizumab s��o 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 sobreviv��ncia. A endostatina foi testada no contexto neoadjuvante com antraciclinas e melhorou a taxa de resposta, mas, mais ensaios s��o necess��rios para estabelecer este f��rmaco. A maioria dos ensaios cl��nicos dos agentes antiangiog��nicos em carcinoma da mama reportaram aumento da taxa de resposta e de sobreviv��ncia livre de doen��a mas nunca aumento da sobreviv��ncia global quando comparado com quimioterapia isolada o que levou ao cepticismo a que assistimos atualmente em rela����o ao bloqueio da angiog��nese. Ensaios cl��nicos selecionados em doentes espec��ficas com objetivos translacionais relacionados com material biol��gico colhido, preferefencialmente em diferentes intervalos da terap��utica, ser��o cruciais para o bloqueio da angiog��nese sobreviver como estrat��gia terap��utica em carcinoma da mama. Cap��tulo 7: A resposta �� hipoxia medeia a resist��ncia prim��ria ao sunitinib em carcinoma da mama localmente avan��ado O sunitinib �� um f��rmaco antiangiog��nico que nunca foi avaliado isolado em doentes com carcinoma da mama n��o tratadas. O nosso objetivo foi caracaterizar a atividade do sunitinib isolado e em combina����o com o docetaxel em carcinoma da mama n��o tratado, localmente avan��ado ou oper��vel, mas de dimens��o 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 combina����o de sunitinib e docetaxel. A resposta, a reist��ncia e a toxicidade foram avaliadas de acordo com parametros cl��nicos, resson��ncia magn��tica nuclear, tomografia de emiss��o de positr��es, histopatologia e perfis de express��o gen��mica. Detet��mos resist��ncia prim��ria ao sunitinib na janela inicial de duas semanas, evidenciada em quatro doentes que n��o responderam. �� data da cirurgia, cinco doentes tinham tumor vi��vel na mama e axila, quatro tinahm tumor vi��vel na mama e tr��s foram retiradas do ensaio. N��o houve respostas patol��gicas completas. A compara����o dos perfis de express��o gen��mica entre os respondedores e os n��o respondedores, aos quinze dias iniciais, permitiu-nos identificar sobre express��o de VEGF e outras vias angiog��nicas nos n��o respondedores. Especificamente, em tumores resistentes ao sunitinib isolado detect��mos uma resposta transcricional �� hipoxia caracterizada por sobre express��o de v��rios dos genes alvo do HIF1��. Neste ensaio de sunitinib isolado em doentes n��o tratadas com carcinoma da mama localmente avan��ado, encontr��mos evid��ncia molecular de resist��ncia prim��ria ao sunitinib possivelmente mediada por sobre express��o de genes que respondem �� hipoxia. Parte 3: Quando parar a terap��utica sist��mica ��s doentes com carcinoma da mama Cap��tulo 8: Agressividade terap��utica ns ��ltimos tr��s meses de vida num estudo retrospetivo dum centro ��nico Inclu��mos todos os adultos que morreram com tumores s��lidos na institui����o em 2003 e foram tratados com quimioterapia para tratar neoplaias metastizadas. Colhemos dados detalhados relacionados com quimioterapia e toxicidade nos ��ltimos tr��s meses de vida a partir do processo cl��nico. Trezentas e dezanove doentes foram inclu��dos, a mediana de idade foi 61 anos. A mediana de sobreviv��ncia de doen��a metast��tica foi de 11 meses. 66% (211) dos doentes foram tratados com QT nos ��ltimos 3 meses de vida, 37% foram tratados com QT no ��limo m��s de vida e 21% nas ��ltimas duas semanas. Nos doentes que foram tratados com QT nos ��ltimos tr��s meses de vida, 50% come��aram um novo regime terap��utico neste per��odo e 14% come��aram um novo regime no ��ltimo m��s. Identific��mos como determinantes de tratamento com QT no fim de vida a idade jovem, o carcinoma da mama, do ov��rio e do p��ncreas. Conclu��mos que administr��mos QT no fim de vida frequentemente e inici��mos novos regimes terap��uticos no ��ltimo m��s de vida em 14% dos casos. Precisamos de aprofundar este trabalho para compreender se esta atitude agressiva resulta em melhor palia����o de sintomas e qualidade de vida no fim de vida dos doentes com neoplasias disseminadas. Cap��tulo 9: O tratamento do carcinoma da mama no fim de vida est�� a mudar? Quis��mos caracterizar a modifica����o da tend��ncia no uso de QT e de estrat��gias paliativas no fim de vida das doentes com carcinoma da mama em diferentes institui����es e em intervalos de tempo diferentes. Para isto selecion��mos doentes que morreram de carcinoma da mama durante 6 anos, entre 2007 e 2012, num hospital geral e compar��mos com as doentes que morreram de carcinoma da mama em 2003 num centro oncol��gico. Avali��mos um total de 232 doentes. O grupo mais recente tem 114 doentes e o grupo anterior tem 118 doentes. Us��mos estat��stica descritiva para caracterizar QT no fim de vida e o uso de estrat��gias paliativas. Ambas as coortes s��o compar��veis em termos das caracter��sticas do carcinoma da mama. Observ��mos aumento do uso de estat��gias paliativas: consulta da dor, consulta de cuidados paliativos e radioterapia paliativa no cuidado das doentes com carcinoma da mama metastizado. Evidenci��mos aumento do n��mero de mortes em servi��os de cuidados paliativos. No entanto, a QT paliativa continua a ser prolongada at�� aos ��ltimos meses de vida, embora tenhamos mostrado uma diminui����o desta pr��tica. Outros indicadores de agressividade como a admiss��o hospitalar tamb��m mostraram diminui����o. Confirm��mos a nossa hip��tese de que h�� maior integra����o da medicina paliativa multidisciplinar e menos agressividade na terap��utica sist��mica das doentes com carcinoma da mama nos ��ltimos meses de vida. Chapter 10: Porque �� que os nossos doentes s��o tratados com quimioterapia at�� ao fim da vida? (editorial) Este cap��tulo come��a por dar o exmeplo duma jovem de 22 anos que viveu tr��s meses ap��s come��ar QT paliatva. Este caso epitomiza a futilidade terap��utica e �� usado como ponto de partida para explorar as raz��es pelas quais administramos QT no fim de vida aos doentes quando �� in��til, t��xica, logisticamente complexa e cara. Ser�� que estamos a prescrever QT at�� tarde demais? Os oncologistas fazem previs��es excessivamente otimistas e t��m uma atitude pr�� terap��utica excessiva e s��o criticados por outros intervenientes nas institui����es de sa��de por isto. Crescentemente doentes, familiares, associa����es de doentes, definidores de pol��ticas de sa��de, jornalistas e a sociedade em geral afloram este tema mas tornam-se inconsistentes quando se trata dum doente pr��ximo em que se modifica o discurso para que se fa��am terap��uticas sit��micas agressivas. H�� uma crescente cultura de preserva����o da qualidade de vida, palia����o, abordagem sintom��tica, referencia����o a unidades de cuidados paliativos e outros temas do fim de vida dos doentes oncol��gicos terminais. Infelizmente, este tema tem ganhado momentum n��o porque os oncologistas estejam a refletir criticamente sobre a sua pr��tica, mas porque os custos dos cuidados de sa��de s��o crescentes e incomport��veis. Seja qual f��r o motivo, as raz��es que levam os oncologistas a administrar QT no fim de vida devem ser criticamente elucidadas. Mas h�� poucos dados para nos guiar nesta fase delicada da vida dos doentes e os que existem s��o por vezes irreconcili��veis, �� uma revis��o destes dados que foi feita neste cap��tulo. Conclus��o: A abordagem do carcinoma da mama no futuro? Na conclus��o, tenta-se olhar para o futuro e prever como ser�� a tomada a cargo dum doente com carcioma da mama amanh��. Faz-se uma avalia����o das v��rias ��reas desde preven����o, rastreio, suscetibilidade gen��tica e comportamental e terap��utica. Na terap��utica separa-se a terap��utica locoregional, sist��mica adjuvante e da doen��a metastizada. Nos tr��s ��ltimos par��grafos a hist��ria duma mulher com um carcinoma localmente avan��ado que sobre expressa o recetor Her2, serve como ilustra����o de como devemos estar preparados para incorporar evolu����o, 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 HIF1�� 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 patients�� 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 patients�� 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.