Estimation du paramètre d'une copule archimedienne en présence de censure dépendante

Les méthodes classiques d’analyse de survie notamment la méthode non paramétrique de Kaplan et Meier (1958) supposent l’indépendance entre les variables d’intérêt et de censure. Mais, cette hypothèse d’indépendance n’étant pas toujours soutenable, plusieurs auteurs ont élaboré des méthodes pour prendre en compte la dépendance. La plupart de ces méthodes émettent des hypothèses sur cette dépendance. Dans ce mémoire, nous avons proposé une méthode d’estimation de la dépendance en présence de censure dépendante qui utilise le copula-graphic estimator pour les copules archimédiennes (Rivest etWells, 2001) et suppose la connaissance de la distribution de la variable de censure. Nous avons ensuite étudié la consistance de cet estimateur à travers des simulations avant de l’appliquer sur un jeu de données réelles.

Improving risk stratification in non-ST-segment elevation myocardial infarction with combined assessment of GRACE and CRUSADE risk scores

BACKGROUND: Risk assessment is fundamental in the management of acute coronary syndromes (ACS), enabling estimation of prognosis. AIMS: To evaluate whether the combined use of GRACE and CRUSADE risk stratification schemes in patients with myocardial infarction outperforms each of the scores individually in terms of mortality and haemorrhagic risk prediction. METHODS: Observational retrospective single-centre cohort study including 566 consecutive patients admitted for non-ST-segment elevation myocardial infarction. The CRUSADE model increased GRACE discriminatory performance in predicting all-cause mortality, ascertained by Cox regression, demonstrating CRUSADE independent and additive predictive value, which was sustained throughout follow-up. The cohort was divided into four different subgroups: G1 (GRACE<141; CRUSADE<41); G2 (GRACE<141; CRUSADE≥41); G3 (GRACE≥141; CRUSADE<41); G4 (GRACE≥141; CRUSADE≥41). RESULTS: Outcomes and variables estimating clinical severity, such as admission Killip-Kimbal class and left ventricular systolic dysfunction, deteriorated progressively throughout the subgroups (G1 to G4). Survival analysis differentiated three risk strata (G1, lowest risk; G2 and G3, intermediate risk; G4, highest risk). The GRACE+CRUSADE model revealed higher prognostic performance (area under the curve [AUC] 0.76) than GRACE alone (AUC 0.70) for mortality prediction, further confirmed by the integrated discrimination improvement index. Moreover, GRACE+CRUSADE combined risk assessment seemed to be valuable in delineating bleeding risk in this setting, identifying G4 as a very high-risk subgroup (hazard ratio 3.5; P<0.001). CONCLUSIONS: Combined risk stratification with GRACE and CRUSADE scores can improve the individual discriminatory power of GRACE and CRUSADE models in the prediction of all-cause mortality and bleeding. This combined assessment is a practical approach that is potentially advantageous in treatment decision-making.

Outcomes of a general hospital-based Home Parenteral Nutrition (HPN) program: report of our experience from a 26-year period

Background: Home parenteral nutrition (HPN) was introduced in Spain in the late 1980s. Our hospital was a pioneering medical centre in this field. Aim: Analyze outcomes of our HPN program. Methods: Retrospective study of patients receiving HPN between 1986-2012. Study variables are expressed as frequency, mean ± SD (range), median [interquartile range]. Parametrics, non-parametrics test and survival analysis (p < 0.05) were applied. Results: 91 patients (55 females and 36 males, mean age: 50.6 ± 5 yrs.) who received HPN for an accrual period of 55,470 days (median: 211 days [range: 63-573]) were included. The most prevalent underlying condition was cancer (49.5%), with the commonest HPN indication being short bowel syndrome (41.1%). The most frequently used catheter type was the tunneled catheter (70.7%). The complication rate was 3.58/1,000 HPN days (2.68, infection; 0.07, occlusion; 0.07 thrombosis; and 0.59, metabolic complications). Complications were consistently associated with both the underlying condition and HPN length. Infections were most frequent within the first 1,000 days of HPN. Liver disease incidence was related to HPN duration. HPN could be discontinued in 42.3% of patients. Ten-year survival rate was 42%, and varied across the underlying conditions. Conclusions: In the present series, the commonest reason for HPN was cancer. Our complication rate is in keeping with that reported in the literature. The overall survival rate was 42%, and varied across the underlying conditions.

Exploring the potential role of allostatic load biomarkers in risk assessment of patients presenting with depressive symptoms

Background: Depression is a major health problem worldwide and the majority of patients presenting with depressive symptoms are managed in primary care. Current approaches for assessing depressive symptoms in primary care are not accurate in predicting future clinical outcomes, which may potentially lead to over or under treatment. The Allostatic Load (AL) theory suggests that by measuring multi-system biomarker levels as a proxy of measuring multi-system physiological dysregulation, it is possible to identify individuals at risk of having adverse health outcomes at a prodromal stage. Allostatic Index (AI) score, calculated by applying statistical formulations to different multi-system biomarkers, have been associated with depressive symptoms. Aims and Objectives: To test the hypothesis, that a combination of allostatic load (AL) biomarkers will form a predictive algorithm in defining clinically meaningful outcomes in a population of patients presenting with depressive symptoms. The key objectives were: 1. To explore the relationship between various allostatic load biomarkers and prevalence of depressive symptoms in patients, especially in patients diagnosed with three common cardiometabolic diseases (Coronary Heart Disease (CHD), Diabetes and Stroke). 2 To explore whether allostatic load biomarkers predict clinical outcomes in patients with depressive symptoms, especially in patients with three common cardiometabolic diseases (CHD, Diabetes and Stroke). 3 To develop a predictive tool to identify individuals with depressive symptoms at highest risk of adverse clinical outcomes. Methods: Datasets used: ‘DepChron’ was a dataset of 35,537 patients with existing cardiometabolic disease collected as a part of routine clinical practice. ‘Psobid’ was a research data source containing health related information from 666 participants recruited from the general population. The clinical outcomes for 3 both datasets were studied using electronic data linkage to hospital and mortality health records, undertaken by Information Services Division, Scotland. Cross-sectional associations between allostatic load biomarkers calculated at baseline, with clinical severity of depression assessed by a symptom score, were assessed using logistic and linear regression models in both datasets. Cox’s proportional hazards survival analysis models were used to assess the relationship of allostatic load biomarkers at baseline and the risk of adverse physical health outcomes at follow-up, in patients with depressive symptoms. The possibility of interaction between depressive symptoms and allostatic load biomarkers in risk prediction of adverse clinical outcomes was studied using the analysis of variance (ANOVA) test. Finally, the value of constructing a risk scoring scale using patient demographics and allostatic load biomarkers for predicting adverse outcomes in depressed patients was investigated using clinical risk prediction modelling and Area Under Curve (AUC) statistics. Key Results: Literature Review Findings. The literature review showed that twelve blood based peripheral biomarkers were statistically significant in predicting six different clinical outcomes in participants with depressive symptoms. Outcomes related to both mental health (depressive symptoms) and physical health were statistically associated with pre-treatment levels of peripheral biomarkers; however only two studies investigated outcomes related to physical health. Cross-sectional Analysis Findings: In DepChron, dysregulation of individual allostatic biomarkers (mainly cardiometabolic) were found to have a non-linear association with increased probability of co-morbid depressive symptoms (as assessed by Hospital Anxiety and Depression Score HADS-D≥8). A composite AI score constructed using five biomarkers did not lead to any improvement in the observed strength of the association. In Psobid, BMI was found to have a significant cross-sectional association with the probability of depressive symptoms (assessed by General Health Questionnaire GHQ-28≥5). BMI, triglycerides, highly sensitive C - reactive 4 protein (CRP) and High Density Lipoprotein-HDL cholesterol were found to have a significant cross-sectional relationship with the continuous measure of GHQ-28. A composite AI score constructed using 12 biomarkers did not show a significant association with depressive symptoms among Psobid participants. Longitudinal Analysis Findings: In DepChron, three clinical outcomes were studied over four years: all-cause death, all-cause hospital admissions and composite major adverse cardiovascular outcome-MACE (cardiovascular death or admission due to MI/stroke/HF). Presence of depressive symptoms and composite AI score calculated using mainly peripheral cardiometabolic biomarkers was found to have a significant association with all three clinical outcomes over the following four years in DepChron patients. There was no evidence of an interaction between AI score and presence of depressive symptoms in risk prediction of any of the three clinical outcomes. There was a statistically significant interaction noted between SBP and depressive symptoms in risk prediction of major adverse cardiovascular outcome, and also between HbA1c and depressive symptoms in risk prediction of all-cause mortality for patients with diabetes. In Psobid, depressive symptoms (assessed by GHQ-28≥5) did not have a statistically significant association with any of the four outcomes under study at seven years: all cause death, all cause hospital admission, MACE and incidence of new cancer. A composite AI score at baseline had a significant association with the risk of MACE at seven years, after adjusting for confounders. A continuous measure of IL-6 observed at baseline had a significant association with the risk of three clinical outcomes- all-cause mortality, all-cause hospital admissions and major adverse cardiovascular event. Raised total cholesterol at baseline was associated with lower risk of all-cause death at seven years while raised waist hip ratio- WHR at baseline was associated with higher risk of MACE at seven years among Psobid participants. There was no significant interaction between depressive symptoms and peripheral biomarkers (individual or combined) in risk prediction of any of the four clinical outcomes under consideration. Risk Scoring System Development: In the DepChron cohort, a scoring system was constructed based on eight baseline demographic and clinical variables to predict the risk of MACE over four years. The AUC value for the risk scoring system was modest at 56.7% (95% CI 55.6 to 57.5%). In Psobid, it was not possible to perform this analysis due to the low event rate observed for the clinical outcomes. Conclusion: Individual peripheral biomarkers were found to have a cross-sectional association with depressive symptoms both in patients with cardiometabolic disease and middle-aged participants recruited from the general population. AI score calculated with different statistical formulations was of no greater benefit in predicting concurrent depressive symptoms or clinical outcomes at follow-up, over and above its individual constituent biomarkers, in either patient cohort. SBP had a significant interaction with depressive symptoms in predicting cardiovascular events in patients with cardiometabolic disease; HbA1c had a significant interaction with depressive symptoms in predicting all-cause mortality in patients with diabetes. Peripheral biomarkers may have a role in predicting clinical outcomes in patients with depressive symptoms, especially for those with existing cardiometabolic disease, and this merits further investigation.

Does prenatal diagnosis modify neonatal treatment and early outcome of children with esophageal atresia?

International audience

Análise comportamental : um estudo por análise de sobrevivência, aplicada a cartões de crédito

A capacidade de adaptação e rapidez de decisão, distinguem as empresas que melhor conseguem competir e crescer no mercado global. Para atuar rapidamente, as organizações precisam de sistemas de informação cada vez mais eficazes, surgindo recentemente uma nova função considerada fundamental para as empresas, que é a de Cientista de Dados. É neste contexto e para responder aos desafios atuais e futuros, que surgem sistemas de informação cada vez mais avançados, suportados por modelos de análise e visualização estatística. Este trabalho consiste em criar uma metodologia de desenvolvimento de modelos de previsão de incumprimento e perfil do consumidor, aplicado a cartões de crédito, com base numa exposição de análise comportamental, utilizando técnicas de análise de sobrevivência. São definidas técnicas de tratamento dos dados recolhidos, estimado modelo não-paramétrico de Kaplan-Meier e vários modelos de Cox de riscos proporcionais. Com recurso à curva ROC, dependente do tempo, à AUC e ao índice de Gini, conclui-se que o modelo final apresenta um desempenho positivo para identificar os clientes em situação de incumprimento ou com propensão a incumprir.

Análise de sobrevivência ao cancro colo-retal nos períodos 2000-2001 e 2007-2008 na região norte de Portugal

O cancro colo-retal é um dos tipos de cancro mais comuns, em ambos os sexos, tendo em conta os dados existentes nos registos oncológicos nas mais diversas regiões do globo, facto que acontece também na região Norte de Portugal. O objetivo desta dissertação foi utilizar métodos de análise de sobrevivência tradicional e de análise de sobrevivência relativa, em dados do cancro colo-retal, considerando um período de observação de 5 anos. Os dados analisados são provenientes do Registo Oncológico Regional do Norte (RORENO), obtendo-se, após inspeção e tratamento prévio, um total de 2855 pacientes aos quais foi diagnosticado cancro colo-retal em dois períodos distintos, 2000-2001 e 2007- 2008. Pretendeu-se também determinar de que forma as covariáveis influenciam a sobrevivência, e como esta evoluiu entre essas duas coortes. Dado não existir informação sobre as causas de morte, foi objetivo deste estudo estimar que parte da mortalidade observada se deve à doença em questão e que parte se deve a outras causas que afetam a mortalidade da população geral. Foram, também, estimados os coeficientes das covariáveis consideradas para os modelos adotados. Todos os resultados foram obtidos utilizando como recurso o software R e seus pacotes adequados. Utilizaram-se diversos métodos tais como Kaplan-Meier, Cox, Ederer II e Net Survival, sendo este último considerado o mais adequado a este tipo de estudo pois é considerado pela comunidade científica o único estimador centrado para análise de sobrevivência relativa e cujas propriedades estatísticas permitem a sua utilização em estudos comparativos entre países. Verificou-se, por este estimador, que não existem diferenças significativas na sobrevivência em função do sexo, idade, distrito ou localização do cancro (cólon ou reto). Por outro lado verificaram-se diferenças significativas para a sobrevivência em função do estadio e das coortes, registando-se um acréscimo global de 8.5% na sobrevivência aos 5 anos de 2000-2001 para 2007-2008. Por fim destacam-se alguns aspetos que merecem atenção em estudos futuros.

Critical energy deficit and mortality in critically ill patients

Objective: We investigate the influence of caloric and protein deficit on mortality and length of hospital stay of critically ill patients. Methods: A cohort prospective study including 100 consecutive patients in a tertiary intensive care unit (ICU) receiving enteral or parenteral nutrition. The daily caloric and protein deficit were collected each day for a maximum of 30 days. Energy deficits were divided into critical caloric deficit (≥ 480 kcal/day) and non-critical caloric deficit (≤ 480 kcal/day); and in critical protein deficit (≥ 20 g/day) and non-critical protein deficit (≤ 20 g/day). The findings were correlated with hospital stay and mortality. Results: The mortality rate was 33%. Overall, the patients received 65.4% and 67.7% of the caloric and protein needs. Critical caloric deficit was found in 72% of cases and critical protein deficit in 70% of them. There was a significant correlation between length of stay and accumulated caloric deficit (R = 0.37; p < 0.001) and protein deficit (R = 0.28; p < 0.001). The survival analysis showed that mortality was greater in patients with both critical caloric (p < 0.001) and critical protein deficits (p < 0.01). The Cox regression analysis showed that critical protein deficit was associated with higher mortality (HR 0.25, 95% CI 0.07-0.93, p = 0.03). Conclusions: The incidence of caloric and protein deficit in the ICU is high. Both caloric and protein deficits increase the length of hospital stay, and protein deficit greater than 20 g/day is an independent factor for mortality in critical care unit.

A Retrospective-Longitudinal Examination of the Relationship between Apportionment of Seat Time in Community-College Algebra Courses and Student Academic Performance

During the past decade, there has been a dramatic increase by postsecondary institutions in providing academic programs and course offerings in a multitude of formats and venues (Biemiller, 2009; Kucsera & Zimmaro, 2010; Lang, 2009; Mangan, 2008). Strategies pertaining to reapportionment of course-delivery seat time have been a major facet of these institutional initiatives; most notably, within many open-door 2-year colleges. Often, these enrollment-management decisions are driven by the desire to increase market-share, optimize the usage of finite facility capacity, and contain costs, especially during these economically turbulent times. So, while enrollments have surged to the point where nearly one in three 18-to-24 year-old U.S. undergraduates are community college students (Pew Research Center, 2009), graduation rates, on average, still remain distressingly low (Complete College America, 2011). Among the learning-theory constructs related to seat-time reapportionment efforts is the cognitive phenomenon commonly referred to as the spacing effect, the degree to which learning is enhanced by a series of shorter, separated sessions as opposed to fewer, more massed episodes. This ex post facto study explored whether seat time in a postsecondary developmental-level algebra course is significantly related to: course success; course-enrollment persistence; and, longitudinally, the time to successfully complete a general-education-level mathematics course. Hierarchical logistic regression and discrete-time survival analysis were used to perform a multi-level, multivariable analysis of a student cohort (N = 3,284) enrolled at a large, multi-campus, urban community college. The subjects were retrospectively tracked over a 2-year longitudinal period. The study found that students in long seat-time classes tended to withdraw earlier and more often than did their peers in short seat-time classes (p < .05). Additionally, a model comprised of nine statistically significant covariates (all with p-values less than .01) was constructed. However, no longitudinal seat-time group differences were detected nor was there sufficient statistical evidence to conclude that seat time was predictive of developmental-level course success. A principal aim of this study was to demonstrate—to educational leaders, researchers, and institutional-research/business-intelligence professionals—the advantages and computational practicability of survival analysis, an underused but more powerful way to investigate changes in students over time.

Risk of repeated self-harm and associated factors in children, adolescents and young adults

Background: Repeated self-harm represents the single strongest risk factor for suicide. To date no study with full national coverage has examined the pattern of hospital repeated presentations due to self-harm among young people. Methods: Data on consecutive self-harm presentations were obtained from the National Self-Harm Registry Ireland. Socio-demographic and behavioural characteristics of individuals aged 10–29 years who presented with self-harm to emergency departments in Ireland (2007–2014) were analysed. Risk of long-term repetition was assessed using survival analysis and time differences between the order of presentations using generalised estimating equation analysis. Results: The total sample comprised 28,700 individuals involving 42,642 presentations. Intentional drug overdose was the most prevalent method (57.9%). Repetition of self-harm occurred in 19.2% of individuals during the first year following a first presentation, of whom the majority (62.7%) engaged in one repeated act. Overall, the risk of repeated self-harm was similar between males and females. However, in the 20–24-year-old age group males were at higher risk than females. Those who used self-cutting were at higher risk for repetition than those who used intentional drug overdose, particularly among females. Age was associated with repetition only among females, in particular adolescents (15–19 years old) were at higher risk than young emerging adults (20–24 years old). Repeated self-harm risk increased significantly with the number of previous self-harm episodes. Time differences between first self-harm presentations were detected. Time between second and third presentation increased compared to time between first and second presentation among low frequency repeaters (patients with 3 presentations only within 1 year following a first presentation). The same time period decreased among high frequency repeaters (patients with at least 4 to more than 30 presentations). Conclusion: Young people with the highest risk for repeated self-harm were 15–19-year-old females and 20–24-year-old males. Self-cutting was the method associated with the highest risk of self-harm repetition. Time between first self-harm presentations represents an indicator of subsequent repetition. To prevent risk of repeated self-harm in young people, all individuals presenting at emergency departments due to self-harm should be provided with a risk assessment including psychosocial characteristics, history of self-harm and time between first presentations.

Use of bird carcass removals by urban scavengers to adjust bird-window collision estimates

Carcass removal by scavengers has been identified as one of the largest biases in estimating bird mortality from anthropogenic sources. Only two studies have examined carcass removal by scavengers in an urban environment, and previous estimates of bird-window collision mortality at houses have relied on carcass removal rates from wind turbine studies. We placed a bird carcass and time-lapse camera at 44 houses in Edmonton, Alberta. In total, 166 7-day trials were conducted throughout 2015. Time-to-event (survival) analysis was used to identify covariates that affected removal. The carcass removal rate was determined for use in estimating the number of birds killed from bird-window collisions at houses in Alberta. In total, 67.5% of carcasses were removed. The date the carcass was placed, the year the house was built, and the level of development within 50 m of the house were the covariates that had the largest effect on carcass removal. In calculating our removal rate, the number of detected carcasses in the first 24 hours was adjusted by 1.47 to account for removal by scavengers. Previously collected citizen science data were used to create an estimate of 957,440 bird deaths each year in Alberta as a result of bird-window collisions with houses. This number is based on the most detailed bird-window collision study at houses to date and a carcass removal study conducted in the same area. Similar localized studies across Canada will need to be completed to reduce the biases that exist with the previous bird-window collision mortality estimate for houses in Canada.

An investigation of the relationship between the components of tumour microenvironment, signal transduction pathways and outcome in breast cancer

Breast cancer, the most commonly diagnosed type of cancer in women, is a major cause of morbidity and mortality in the western world. Well-established risk factors of breast cancer are mostly related to women’s reproductive history, such as early menarche, late first pregnancy and late menopause. Survival rates have improved due to a combination of factors, including better health education, early detection with large-scale use of screening mammogram, improved surgical techniques, as well as widespread use of adjuvant therapy. At initial presentation, clinicopathological features of breast cancer such as age, nodal status, tumour size, tumour grade, and hormonal receptor status are considered to be the standard prognostic and predictive markers of patient survival, and are used to guide appropriate treatment strategies. Lymphovascular invasion (LBVI), including lymphatic (LVI) and blood (BVI) vessel invasion, has been reported to be prognostic and merit accurate evaluation, particularly in patients with node negative tumours who might benefit from adjuvant chemotherapy. There is a lack of standard assessment and agreement on distinguishing LVI from BVI despite the major challenges in the field. A systematic review of the literatures, examining methods of detection and the prognostic significance of LBVI, LVI and BVI, was carried out. The majority of studies used haematoxylin and eosin (H&E) and classical histochemistry to identify LVI and BVI. Only few recent studies used immunohistochemistry (IHC) staining of the endothelium lining lymphatic and blood vessels, and were able to show clear differences between LVI and BVI. The prognostic significance of LBVI and LVI was well-documented and strongly associated with aggressive features of breast tumours, while the prognostic value and the optimal detection method of BVI were unclear. Assessment and prognostic value of LBVI on H&E sections (LBVIH&E) was examined and compared to that of LVI and BVI detected using IHC with D2-40 for LVI (LVID2–40) and Factor VIII for BVI (BVIFVIII) in patients with breast cancer including node negative and triple negative patients (n=360). LBVIH&E, LVID2–40 and BVIFVIII were present in 102 (28%), 127 (35%) and 59 (16%) patients respectively. In node negative patients (206), LBVIH&E, LVID2–40 and BVIFVIII were present in 41 (20%), 53 (26%) and 21 (10%) respectively. In triple negative patients (102), LBVIH&E, LVID2–40 and BVIFVIII were present in 35 (29%), 36 (35%) and 14 (14%) respectively. LBVIH&E, LVID2–40 and BVIFVIII were all significantly associated with tumour recurrence in all cohorts. On multivariate survival analysis, only LVID2–40 and BVIFVIII were independent predictors of cancer specific survival (CSS) in the whole cohort (P=0.022 and P<0.001 respectively), node negative (P=0.008 and P=0.001 respectively) and triple negative patients (P=0.014 and P<0.001 respectively). Assessment of LVI and BVI by IHC, using D2-40 and Factor VIII, improves prediction of outcome in patients with node negative and triple negative breast cancer and was superior to the conventional detection method. Breast cancer is recognised as a complex molecular disease and histologically identical tumours may have highly variable outcomes, including different responses to therapy. Therefore, there is a compelling need for new prognostic and predictive markers helpful of selecting patients at risk and patients with aggressive diseases who might benefit from adjuvant and targeted therapy. It is increasingly recognised that the development and progression of human breast cancer is not only determined by genetically abnormal cells, but also dependent on complex interactions between malignant cells and the surrounding microenvironment. This has led to reconsider the features of tumour microenvironment as potential predictive and prognostic markers. Among these markers, tumour stroma percentage (TSP) and tumour budding, as well as local tumour inflammatory infiltrate have received recent attention. In particular, the local environment of cytokines, proteases, angiogenic and growth factors secreted by inflammatory cells and stromal fibroblasts has identified crucial roles in facilitating tumour growth, and metastasis of cancer cells through lymphatic and/or blood vessel invasion. This might help understand the underlying process promoting tumour invasion into these vessels. An increase in the proportion of tumour stroma and an increase in the dissociation of tumour cells have been associated with poorer survival in a number of solid tumours, including breast cancer. However, the interrelationship between these variables and other features of the tumour microenvironment in different subgroups of breast cancer are not clear. Also, whether their prognostic values are independent of other components of the tumour microenvironment have yet to be identified. Therefore, the relationship between TSP, clinicopathological characteristics and outcome in patients with invasive ductal breast cancer, in particular node negative and triple negative disease was examined in patients with invasive ductal breast cancer (n=361). The TSP was assessed on the haematoxylin and eosin-stained tissue sections. With a cut-off value of 50% TSP, patients with ≤50% stroma were classified as the low-TSP group and those with >50% stroma were classified as the high-TSP group. A total of 109 (30%) patients had high TSP. Patients with high TSP were old age (P=0.035), had involved lymph node (P=0.049), Her-2 positive tumours (P=0.029), low-grade peri-tumoural inflammatory infiltrate (P=0.034), low CD68+ macrophage infiltrate (P<0.001), low CD4+ (P=0.023) and low CD8+ T-lymphocytes infiltrate (P=0.017), tumour recurrence (P=0.015) and shorter CSS (P<0.001). In node negative patients (n=207), high TSP was associated with low CD68+ macrophage infiltrate (P=0.001), low CD4+ (P=0.040) and low CD8+ T-lymphocytes infiltrate (P=0.016) and shorter CSS (P=0.005). In triple negative patients (n=103), high TSP was associated with increased tumour size (P=0.017) high tumour grade (P=0.014), low CD8+ T-lymphocytes infiltrate (P=0.048) and shorter CSS (P=0.041). The 15-year cancer specific survival rate was 79% vs 21% in the low-TSP group vs high-TSP group. On multivariate survival analysis, a high TSP was associated with reduced CSS in the whole cohort (P=0.007), node negative patients (P=0.005) and those who received systemic adjuvant therapy (P=0.016), independent of other pathological characteristics including local host inflammatory responses. Therefore, a high TSP in invasive ductal breast cancer was associated with recurrence and poorer long-term survival. The inverse relation with the tumour inflammatory infiltrate highlights the importance of the amount of tumour stroma on immunological response in patients with invasive ductal breast cancer. Implementing this simple and reproducible parameter in routine pathological examination may help optimise risk stratification in patients with breast cancer. Similarly, the relationship between tumour budding, clinicopathological characteristics and outcome was examined in patients with invasive ductal breast cancer (n=474), using routine pathological sections. Tumour budding was associated with several adverse pathological characteristics, including positive lymph node (P=0.009), presence of LVI (P<0.001), and high TSP (P=0.001) and low-grade general peri-tumural inflammatory infiltrative (P=0.002). In node negative patients, a high tumour budding was associated with presence of LVI (P<0.001) and low-grade general peri-tumural inflammatory infiltrative (P=0.038). On multivariate survival analysis, tumour budding was associated with reduced CSS (P=0.001), independent of nodal status, tumour necrosis, CD8+ and CD138+ inflammatory cells infiltrate, LVI, BVI and TSP. Furthermore, tumour budding was independently associated with reduced CSS in node negative patients (P=0.004) and in those who have low TSP (P=0.003) and high-grade peri-tumoural inflammatory infiltrative (P=0.012). A high tumour budding was significantly associated with shorter CSS in luminal B and triple negative breast cancer subtypes (all P<0.001). Therefore, tumour budding was a significant predictor of poor survival in patients with invasive ductal breast cancer, independent of adverse pathological characteristics and components of tumour microenvironment. These results suggest that tumour budding may promote disease progression through a direct effect on local and distant invasion into lymph nodes and lymphatic vessels. Therefore, detection of tumour buds at the stroma invasive front might therefore represent a morphologic link between tumour progression, lymphatic invasion, spread of tumour cells to regional lymph nodes, and the establishment of metastatic dissemination. Given the potential importance of the tumour microenvironment, the characterisation of intracellular signalling pathways is important in the tumour microenvironment and is of considerable interest. One plausible signalling molecule that links tumour stroma, inflammatory cell infiltrate and tumour budding is the signal transducer and activator of transcription (STAT). The relationship between total and phosphorylated STAT1 (ph-STAT1), and total and ph-STAT3 tumour cell expression, components of tumour microenvironment and survival in patients with invasive ductal breast cancer was examined. IHC of total and ph-STAT1/STAT3 was performed on tissue microarray of 384 breast cancer specimens. Cellular STAT1 and cellular STAT3 expression at both cytoplasmic and nuclear locations were combined and identified as STAT1/STAT3 tumour cell expression. These results were then related to CSS and phenotypic features of the tumour and host. A high ph-STAT1 and a high ph-STAT3 tumour cell expression was associated with increased ER (P=0.001 and P<0.001 respectively) and PR (all P<0.05), reduced tumour grade (P=0.015 and P<0.001 respectively) and necrosis (all P=0.001). Ph-STAT1 was associated with increased general peri-tumoural inflammatory infiltrate (P=0.007) and ph-STAT3 was associated with lower CD4+ T-lymphocyte infiltrate (P=0.024). On multivariate survival analysis, including both ph-STAT1 and ph-STAT3 tumour cell expression, only high ph-STAT3 tumour cell expression was significantly associated with improved CSS (P=0.010) independent of other tumour and host-based factors. In patients with high necrosis grade, high ph-STAT3 tumour cell expression was independent predictor of improved CSS (P=0.021). Ph-STAT1 and ph-STAT3 were also significantly associated with improved cancer specific survival in luminal A and B subtypes. STAT1 and STAT3 tumour cell expression appeared to be an important determinant of favourable outcome in patients with invasive ductal breast cancer. The present results suggest that STATs may affect disease outcome through direct impact on tumour cells, and the surrounding microenvironment. The above observations of the present thesis point to the importance of the tumour microenvironment in promoting tumour budding, LVI and BVI. The observations from STATs work may suggest that an important driving mechanism for the above associations is the presence of tumour necrosis, probably secondary to hypoxia. Further work is needed to examine the interaction of other molecular pathways involved in the tumour microenvironment, such as HIF and NFkB in patients with invasive ductal breast cancer.

Evaluación de desenlace: trasplante meniscal versus segunda meniscectomía

Introducción: El incremento de pacientes sintomáticos de rodilla y la osteoartrosis en jóvenes con limitadas posibilidades terapéuticas después de una meniscectomía, genera la búsqueda de alternativas terapéuticas. A pesar que es poco utilizado en Colombia, el trasplante meniscal es una propuesta para el manejo sintomático. Según cifras norteamericanas, se practican entre 700.000 a 1.500.000 artroscopias de rodilla anualmente, el 50% termina en meniscectomía y de este un 40% persisten sintomáticos. Métodos: Estudio de cohorte retrospectivo, con el objetivo de evaluar dolor (Escala Visual Análoga-EVA) y funcionalidad (Escala de Tegner y Lysholm) en los pacientes a quienes se les realizó trasplante meniscal o meniscectomía por segunda vez, entre los años 2007 a 2015. Resultados: A partir de los 6 meses la EVA mostró una tendencia a la mejoría en el grupo de trasplante meniscal, pasando de Moderado a Leve (p: <0.000). La Escala de Tegner y Lysholm cambió de Pobre a Bueno en el grupo de segunda meniscectomía (p= 0.008) y de Bueno a Excelente en el grupo trasplantado (p=0.225). La calificación promedio de la EVA en el grupo de trasplante presentó mejoría (p=<0.000), a diferencia del grupo de segunda meniscectomía (p=0.591). La escala de Tegner y Lysholm, mostró significancia estadística con tendencia a la mejoría en el grupo de segunda meniscectomía. Discusión: Los resultados muestran que con trasplante meniscal hay mejoría del dolor y la funcionalidad versus un segunda meniscectomía. Para fortalecer la evidencia de este tratamiento son necesarios estudios prospectivos complementarios.

Supervivencia y mortalidad por tipo de terapia de reemplazo renal, en pacientes con enfermedad renal crónica terminal, en una cohorte de pacientes asegurados en Colombia

En Colombia se ha podido establecer que la incidencia y mortalidad de la Enfermedad Renal Crónica Terminal continúan en aumento en los últimos 6 años a pesar de las estrategias de intervención para prevención y control de la enfermedad implementadas nivel nacional. Este trabajo busca establecer la línea de base para la población asegurada en Colombia, frente a la supervivencia de pacientes en terapia de remplazo renal (TRR).

Experiencia y porcentaje de complicaciones de las derivaciones portosistémicas intrahepáticas transyugulares en la Fundación Cardioinfantil

La derivación portosistémica intrahepática transyugular (TIPS) es una técnica importante en el manejo de las complicaciones de la hipertensión portal, en especial en aquellos pacientes candidatos a trasplante hepático. Se trata de un estudio observacional analítico, sin riesgo, en el cual se emplearon técnicas y métodos de investigación documental retrospectivo, y no se realizó ningún tipo de intervención sobre las variables fisiológicas, psicológicas y sociales de la población incluida. Se realizó la descripción demográfica de los pacientes, características clínicas, hallazgos imageneológicos y aspectos técnicos asociados al procedimiento de los pacientes con hipertensión portal que han sido manejados con TIPS en la Fundación CardioInfantil desde Enero 1 de 2007 hasta Junio 30 de 2016. Se incluyeron 54 pacientes de los cuales el 66,7% no presentaron complicaciones inmediatas, tenidas en cuenta desde la terminación del procedimiento y hasta las siguientes 24 horas; sin embargo, 16,9% debutaron con encefalopatía durante este periodo. De las complicaciones tardías, la más frecuente fue la ascitis con un 66,7%, con una mortalidad de 20,4% de los cuales, el 45% de estos fue por shock séptico y falla orgánica secundaria. Aunque el porcentaje de complicaciones asociadas al procedimiento fue alto en nuestros pacientes, se encuentra dentro de los valores reportados en la literatura. Los resultados presentados son un punto de partida para la evaluación del procedimiento en nuestra población y permiten implementar estrategias de mejora que conlleven a incidir de manera positiva en el porcentaje de complicaciones y mortalidad derivadas del procedimiento.