Introdução: Há poucos dados na literatura sobre a neuropatia periférica (NP) associada ao lúpus eritematoso sistêmico (LES). Objetivo: Descrever a NP atribuída exclusivamente ao LES e avaliar suas características clínicas, laboratoriais, tratamento e evolução a curto e longo prazo. Métodos: Pacientes com LES segundo critérios do American College of Rheumatology (ACR) de 1997, que tiveram NP sintomática comprovada por eletroneuromiografia foram identificados através de revisão do prontuário eletrônico. A NP foi classificada de acordo com a nomenclatura do ACR para síndromes neuropsiquiátricas do LES de 1999. Os critérios de exclusão foram qualquer outra condição clínica associada à ocorrência de NP: comorbidades, deficiência de vitamina B12, uso de drogas (álcool, talidomida, leflunomida, estatinas), infecções e outras doenças autoimunes. Controles com LES sem NP, pareados por idade e sexo, com duração de doença semelhante, foram selecionados. Resultados: NP devido exclusivamente ao LES foi identificada em 38 de 2074 pacientes (1,8%), sendo dois terços nos primeiros cinco anos da doença (63,2%). O tipo mais comum de NP foi a polineuropatia (71,1%), de padrão sensitivo-motor (68,4%). Pacientes com NP relacionada ao LES apresentaram maiores frequências de vasculite cutânea (50% vs. 21,1%, p=0,002), linfopenia (60,5% vs. 36,8%, p=0,027), anti-Sm (52,6% vs. 27,6%, p=0,013) e maiores escores de Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (11,5±10,5 vs. 4,9±6,7; p < 0,0001) comparados aos controles. Os escores de SLEDAI foram ainda mais altos em pacientes com início precoce da NP, com menos de um ano de diagnóstico da doença, comparados a pacientes com NP entre um e cinco anos e após cinco anos do início do LES (21,3±9,1 vs. 8,2±6,6 vs. 3,9±5,3; p < 0,001). Todos os pacientes com NP atribuída ao LES foram tratados com corticóides e 97,4% com terapia imunossupressora: ciclofosfamida intravenosa em 50% e azatioprina em 42,1% dos pacientes. Após um ano de acompanhamento, 92,1% dos pacientes apresentaram uma evolução favorável, com remissão total (36,8%) ou parcial (55,2%) do quadro neuropático, associada a redução da dose de prednisona (48,3±17,9 vs. 15,3±13,4mg/dia; p < 0,0001), da terapêutica sintomática (57,9% vs. 29,7%; p=0,02) e do escore SLEDAI (11,5±10,5 vs. 1,7±3,7; p < 0,0001). O grupo com início precoce da NP teve melhor resposta ao tratamento do que o grupo com início tardio (remissão completa após um ano: 61,5% vs. 25%, p=0,039). Após cinco anos de seguimento, 89,3% mantiveram remissão completa/parcial do quadro. Na análise multivariada, foi confirmada a associação significante entre NP e vasculite cutânea (OR 3,91; IC95% 1,59-9,54; p=0,003), anti-Sm (OR 2,77; IC95% 1,16-6,61; p=0,022) e linfopenia (OR 2,48; IC95% 1,05-5,89; p=0,039). Conclusão: a NP associada exclusivamente ao LES é uma manifestação incomum, caracterizada por um padrão bimodal, com um grupo de início precoce, associado a alta atividade de doença e maior taxa de remissão completa e um grupo de início mais tardio, com resposta parcial ao tratamento imunossupressor. Há um prognóstico geral favorável após um ano de tratamento, sem alterações significativas após cinco anos de seguimento / Introduction: There are few information in the literature regarding peripheral neuropathy (PN) associated to systemic lupus erythematosus (SLE). Objective: To describe PN attributed exclusively to SLE and evaluate its clinical, laboratorial characteristics, treatment, short and long-term outcome. Methods: SLE patients according to 1997 American College of Rheumatology (ACR) criteria were identified using an electronic medical record database. PN diagnosis was defined by neurological abnormalities associated with an altered electroneuromyography and classified according to 1999 ACR nomenclature for neuropsychiatric SLE syndromes. Clinical and laboratory data were evaluated at PN onset and after one and five years. Exclusion criteria were other conditions associated with PN: comorbidities, vitamin B12 deficiency, drugs (alcohol, thalidomide, leflunomide, statin), infections, and other autoimmune diseases. Age- sex- and disease duration-matched SLE patients without PN were selected as controls. Results: Lupus PN was identified in 38 of 2,074 patients (1.8%) and almost two-thirds had PN onset in the first five years of disease (63.2%). The most common type was polyneuropathy (71.1%) with sensory-motor pattern (68.4%). PN SLE had higher frequencies of cutaneous vasculitis (50% vs. 21.1%, p=0.002), lymphopenia (60.5% vs 36.8%, p=0.027), anti-Sm (52.6% vs. 27.6%, p=0.013) and higher Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores (11.5±10.5 vs. 4.9±6.7, p < 0.0001) compared to controls. SLEDAI scores were higher in patients who had PN with less than one year of disease diagnosis, compared to those with PN onset between one and five years or more than five years of SLE (21.3±9.1 vs. 8.2±6.6 vs. 3.9±5.3; p < 0.001). At PN diagnosis, all patients received glucocorticoids and 97.4% started immunosuppressive therapy (50% intravenous cyclophosphamide, 42.1% azathioprine). After one-year follow-up, 92.1% had a favorable outcome with complete (36.8%) or partial remission (55.2%), in parallel with a decrease in prednisone dose (48.3±17.9 vs. 15.3±13.4mg/d, p < 0.0001), symptomatic therapy (57.9% vs. 29.7%, p=0.02), and SLEDAI scores (11.5±10.5 vs. 1.7±3.7, p < 0.001). Early PN onset group had a better response to treatment compared to late PN onset (complete remission at one-year follow-up 61.5% vs. 25%, p=0.039). At five-year, 89.3% remained with complete/partial remission. In multivariate analysis, PN was associated to cutaneous vasculitis (OR 3.91; 95%CI 1.59-9.54; p=0.003), anti-Sm (OR 2.77; 95%CI 1.16-6.61; p=0.022), and lymphopenia (OR 2.48; 95%CI 1.05-5.89; p=0.039). Conclusion: PN attributed to SLE itself is a rare manifestation with a bimodal pattern, characterized by an early onset group associated with high disease activity and a higher rate of complete remission, and a late onset group with low disease activity and a partial therapy response. This study reveals a favorable outcome after one year of immunosuppressive therapy in most PN SLE patients, without significant changes at five years of follow-up

Fundamentos - Identificar pacientes ambulatoriais que necessitam de recursos terciários de hospital de referência voltado para a prática cardiológica é inerente à responsabilidade assistencial. Compete reconhecer pacientes sob maior risco de prognóstico desfavorável, o que pode ser feito pelo emprego de métodos estatísticos tradicionais. Com o mesmo fito, as redes neurais têm sido objeto de interesse. Formulamos a hipótese de que as redes neurais, alimentadas a partir de variáveis selecionadas com o emprego de estatística tradicional, pudessem contribuir para a avaliação prognóstica de pacientes com insuficiência cardíaca. Objetivos - Avaliar o prognóstico de pacientes com diagnóstico de insuficiência cardíaca com o emprego de métodos da estatística de sobrevivência associada com a rede neural artificial. Delineamento - Estudo de coorte retrospectiva a partir de dados assistenciais de pacientes que receberam o diagnóstico de insuficiência cardíaca, identificação das variáveis associadas ao prognóstico com o emprego da estatística tradicional e alimentação da rede neural perceptron de múltiplas camadas (Neuro XL Predictor - OLSOFT Software Development) com essas variáveis. Local - Ambulatório cardiológico com alto volume de atendimentos voltado para pacientes do Sistema Único de Saúde (SUS) em hospital acadêmico de referência terciário. Participantes - 2.128 pacientes consecutivos, que receberam o diagnóstico de insuficiência cardíaca de 2 de julho de 2003 a 2 de julho de 2007. Desfecho - óbito por qualquer causa. Análise de dados - À análise descritiva e exploratória, seguiu-se a avaliação da probabilidade de sobrevida pelo método de Kaplan Meier, seguida de análise inferencial com o emprego do teste de log-rank e do modelo de riscos proporcionais de Cox. Identificadas as variáveis associadas ao prognóstico de sobrevida, foi desenvolvida a rede neural nas diferentes fases de aprendizado- treinamento e com o recurso do algoritmo de treinamento backpropagation. A rede neural foi desenvolvida em cinco fases: fase 1 - aprendizado-treinamento (n=968 óbitos com informação completa); fase 2 - avaliação e aplicação (pacientes vivos até 2012); fase 3 - comparação da previsão de sobrevida com o emprego rede ( pacientes vivos até 2012) com a sobrevida observada; fase 4 - reensaios para aprendizados com novos desfechos (óbitos em 2013 e 2014); fase 5 - avaliação do aprendizado da rede na fase 4 (pacientes vivos e falecidos). A acurácia, a sensibilidade, a especificidade, o valor preditivo positivo e o valor preditivo negativo dos melhores modelos na previsão da sobrevida obtidas com a rede neural foram avaliados, considerando as duas funções de ativação (tangente hiperbólica e zero-based log sigmoid). Para tanto, foi preciso determinar intervalos de corte definidos por critério clínico de razoabilidade de expectativa do tempo de sobrevida e acerto calculado pela rede. A estimativa da previsibilidade e do erro também foi avaliada com o emprego da função de perda. Resultados - A análise estatística (n=2.128 pacientes) revelou as seguintes variáveis associadas ao prognóstico: idade (p < 0,001), índice de massa corpórea (p < 0,001), pressão arterial diastólica (p < 0,001), etiologia da insuficiência cardíaca (p < 0,001), classe funcional (p < 0,001), espessura do septo interventricular (p=0,037), diâmetro diastólico do ventrículo esquerdo (p < 0,001), diâmetro do átrio esquerdo (p=0,025), potássio sérico (p=0,015), colesterol total (p < 0,001), creatinina (p < 0,001) e a presença de diabetes melito (p=0,034). Os modelos de redes neurais com melhor previsibilidade foram obtidos pela categorização do tempo de sobrevida inferior a 2 anos, entre 2 anos e 6 anos, e superior a 6 anos. Nos pacientes com tempo de sobrevida observado superior a 6 anos, a partir da consulta inicial, com intervalo de corte de 3 anos, a estimativa feita com o emprego da rede neural demonstrou sensibilidade 93,0% (com ambas as funções de ativação), especificidade 76,4% ou 77,5% (dependendo da função de ativação), valor preditivo negativo 97,4% (com ambas as funções de ativação) e valor preditivo positivo 53,6% ou 54,7% (dependendo da função de ativação). Nos pacientes com tempo de sobrevida observado entre 2 anos e 6 anos, a partir da data do início dos sintomas, com intervalo de corte de 2 anos, obtivemos sensibilidade 89,8% (com ambas as funções de ativação), especificidade 72,5% ou 76,5%, valor preditivo positivo 86,3% ou 88,0% e valor preditivo negativo 78,7% ou 79,6% (dependendo da função de ativação). Nos pacientes com tempo de sobrevida observado inferior a 2 anos, a partir da data do início dos sintomas, com intervalo de corte de 1 ano, a estimativa com o emprego da rede neural demonstrou sensibilidade 87,2% (com ambas as funções de ativação), especificidade de 62,5% ou 66,7% (dependendo da função de ativação), valor preditivo positivo 82,0% ou 83,7% (dependendo da função de ativação) e valor preditivo negativo 71,4% ou 72,7% (dependendo da função de ativação). O erro da previsão de sobrevida com o emprego da rede neural, estimado com o auxílio da função de perda, variou de 4,4 meses até 1,1 anos. Conclusões - O emprego da rede neural alimentada por variáveis selecionadas com o emprego de estatística de sobrevivência tradicional pode ser método profícuo na avaliação prognóstica de pacientes com insuficiência cardíaca. A previsibilidade de estimativa de sobrevida alcançada com o uso de rede neural foi menor nos pacientes com quadros clínicos de menor tempo de evolução, comparativamente aos pacientes com maior tempo de evolução; no primeiro caso permitiria sugerir quadros mais instáveis em relação aos casos mais estáveis, isto é, aqueles com tempo de evolução maior / Background - Identifying outpatients who need tertiary resources of a referral cardiology hospital includes recognizing those at higher risk of unfavorable prognosis. Studies aimed at this objective may be accomplished with traditional statistics. Neural networks have been studied as a promising tool in the assessment of patients´ prognosis. We hypothesized that the neural networks developed with variables selected through traditional statistics might contribute to the prognostic evaluation of patients with heart failure. Objectives - To evaluate the prognosis of patients with heart failure using methods of survival statistics combined with the resources of artificial neural networks. Design - Retrospective cohort study from a database of patients previously diagnosed with heart failure, identification of variables associated with prognosis using traditional statistics, development of a neural network perceptron of multiple layers (Neuro XL Predictor - OLSOFT Software Development) with these variables. Setting - outpatient clinic from an academic tertiary cardiology center Participants - 2128 consecutive patients who received the diagnosis of heart failure between July 2, 2003 and July 2, 2007. Outcomes - death for any cause. Data analysis - Statistical evaluation was performed for descriptive and exploratory analysis and was followed by Kaplan Meier survival probability, and inferential analysis using the log-rank test and the Cox proportional hazards model to identify the variables associated with prognosis. Variables thus selected were then input for the neural network in the different stages of learning-training, with the backpropagation algorithm. The neural network was developed in 5 phases: phase 1 - learning / training (n = 968 deaths with complete information); phase 2 - evaluation and application (patients alive until 2012); phase 3 - comparison of the predicted versus the observed survival using the network (patients alive until 2012); phase 4 - re-tests for learning with new outcomes (deaths in 2013 and 2014); phase 5 - assessment of network learning in phase 4 (living and deceased patients). The accuracy, sensitivity, specificity, positive predictive value and negative predictive value of the best models in the prediction of survival obtained with the neural network were evaluated taking into account the two activation functions (hyperbolic tangent and zero-based log sigmoid) and the cut-off intervals defined by clinical criteria of reasonableness of expected survival time and the estimated estimate by the network. The estimation of predictability and error was also evaluated using the loss function. Results - Statistical analysis (n = 2128 patients) revealed the following variables associated with prognosis: age (p < 0.001), body mass index (p < 0.001), diastolic blood pressure (p < 0.001), heart failure etiology (P < 0.001), functional class (p < 0.001), interventricular septum thickness (p = 0.037), left ventricular diastolic diameter (p < 0.001), left atrial diameter (p = 0.025), serum potassium level, total cholesterol (p < 0.001), serum creatinine level (p < 0.001) and the presence of diabetes mellitus (p = 0.034). The models of neural networks with better predictability were obtained with the categorization of the survival time of less than 2 years, between 2 and 6 years, and over 6 years. In patients with a survival time of more than 6 years from the initial consultation, with a cut-off interval of 3 years (or 1095 days), the estimate using the neural network showed sensitivity 93.0% (with both activation functions), specificity of 76.4% or 77.5% (depending on the activation function), negative predictive value 97.4% (with both activation functions) and positive predictive value 53.6% or 54.7% (depending on the function of activation). In patients with a survival time of 2 to 6 years from the onset of symptoms, with a cut-off interval of 2 years (or 730 days), we obtained 89.8% sensitivity (with both activation functions), specificity 72,5% or 76.5%, positive predictive value 86.3% or 88.0% and negative predictive value 78.7% or 79.6% (depending on the activation function). In patients with a survival time of less than 2 years from the onset of symptoms, with a cut-off interval of 1 year (or 365 days), the estimate using the neural network showed a sensitivity of 87.2% (with both activation functions), specificity of 62.5% or 66.7% (depending on the activation function), positive predictive value 82.0% or 83.7% (depending on the activation function) and negative predictive value 71.4% or 72.7% (depending on the activation function). The error of survival prediction with the use of the estimated neural network with the aid of the function of absolute loss ranged from 4.4 months to 1.1 years. Conclusions - The use of selected variables input in the neural network with the use aid of traditional survival statistics, may be a useful method for the prognostic evaluation of patients with heart failure. Estimates were less accurate in patients with a shorter duration of symptoms relative to those with symptoms for a long time; in the first case it would suggest more unstable disease relative to those with more stable disease, namely with symptoms for a long time

Contexte : L'insuffisance cardiaque (IC) est un syndrome aux étiologies variées, et hétérogène dans ses présentations cliniques, dont l'incidence augmente avec l'âge et dont le pronostic reste sombre. Les facteurs pronostiques dans l'IC ont été largement décrits dans la littérature, en particulier dans l'IC à fraction d'éjection réduite (ICFER), à plus ou moins long terme. Des interventions thérapeutiques médicamenteuses, chirurgicales, ou complexes sont recommandées pour traiter ce syndrome. Objectifs : Les objectifs de ce travail étaient d'évaluer la valeur pronostique des marqueurs de fibrose chez les patients hypertendus, de décrire la survie et d'identifier les facteurs pronostiques chez les patients en IC, à très long terme chez les ICFER, et à 1 an chez les IC à fraction d'éjection préservée (ICFEP), et de mesurer l'impact sur les hospitalisations de 2 interventions complexes recommandées. Méthodes : Une première étude de cohorte a été menée chez des patients hypertendus, avec un recueil à l'inclusion des dosages sériques des marqueurs du renouvellement de la matrice extracellulaire cardiaque (MRMEC) et un suivi pendant 6 ans. Deux autres études de cohorte ont permis d'identifier les facteurs pronostiques de décès à 15 ans chez des patients ICFER (EPICAL), et à 1 an chez les ICFEP (Odin). Enfin, les données du PMSI ont permis de mesurer l'impact pronostique de la prise en charge dans une unité spécialisée (UTIC) et d'une prise en charge de type disease management (ICALOR). Résultats : La première étude a mis en évidence la valeur pronostique des MRMEC chez des patients hypertendus. L'étude EPICAL a montré que l'âge avancé, le diabète, l'insuffisance rénale chronique, l'ancienneté de l'IC, les antécédents de décompensation, la tachycardie, une fraction d'éjection réduite, et une hyponatrémie étaient associés à une mortalité plus élevée à 15 ans chez les ICFER. L'étude ODIN a montré la valeur pronostique négative de facteurs sociaux comme le fait de vivre seul ou la limitation des activités, chez les ICFEP. Enfin, les prises en charge en UTIC et par le réseau ICALOR étaient associées à une diminution des hospitalisations pour IC, mesurable à l'échelle populationnelle. Conclusion : Ces travaux permettent d'envisager de nouvelles pistes de prévention primaire et secondaire, afin de diminuer l'incidence, la morbidité et la mortalité liées à l'IC / Context: Heart failure (HF) is a heterogeneous syndrome with various aetiologies. HF incidence increases with age, and the prognosis remains poor. Prognostic factors have been widely described in the literature, especially in HF with reduced ejection fraction with short-term or mid-term follow-up. Medications, surgical interventions, and complex interventions are part of the current guidelines. Objectives: To assess the prognostic value of fibrosis markers in hypertensive patients; to describe the survival and to detect prognostic factors, first at 15 years in HF patients with reduced ejection fraction (HFREF), and second at one year in HF patients with preserved ejection fraction (HFPEF); and to assess the prognostic impact of 2 complex interventions on HF hospitalisations. Methods: Cardiac extracellular matrix serum markers (CEMSM) were assessed at baseline in a first cohort of hypertensive patients followed-up for 6 years. Two other cohort studies were used to detect prognostic factors associated with very-long term mortality in HFREF (EPICAL), and with 1-year mortality in HFPEF (Odin). And the national diagnostic related group database was used to assess the prognostic impact of a HF unit (UTIC) and a disease management programme (ICALOR). Results: The first cohort study highlighted the prognostic value of CEMSM in hypertensive patients. In EPICAL study, older age, diabetes mellitus, chronic renal failure, time from HF onset, history of hospitalisations for worsening HF, tachycardia, a low left ventricular ejection fraction, and hyponatraemia were associated with a higher mortality in HFREF patients. In Odin study, we highlighted the negative prognostic impact of social factors, such as living alone or daily activity limitation, in HFPEF patients. Both UTIC and ICALOR were associated with a decrease in HF hospitalisations compatible with a population impact. Conclusion: These studies offer new insights for primary and secondary prevention strategies that could eventually lead to decrease HF incidence, HF morbidity, and HF mortality

Avec une prévalence mondiale de 0,7%, l’infection in utero à cytomégalovirus (CMV) représente la première cause de handicap neurologique congénital d’origine infectieuse. Les modalités de prise en charge de cette infection restent débattues notamment en raison de l’absence de marqueurs pronostics fiables et d’inconnus sur sa physiopathologie notamment celle de l’atteinte du cerveau fœtal. Le premier objectif de notre travail était de décrire et valider des marqueurs immuno-virologiques prédictifs de la transmission verticale et de séquelles néonatales. Le deuxième objectif était d’étudier les corrélats immuno-virologiques in situ de la sévérité de l’atteinte du cerveau fœtal. Nous avons pu établir à partir du bilan virologique maternel (avidité des IgG et ADN CMV sanguin) un score de risque de transmission verticale du virus en cas de primo-infection maternelle. Nous avons montré que le niveau du réservoir viral fœtal, reflété par la charge virale dans le liquide amniotique et dans le sang fœtal, était un marqueur prédictif des séquelles néonatales. Ainsi, la combinaison de la mesure du réservoir viral fœtal avec l’imagerie fœtale a permis d’établir des scores pronostics avec des valeurs prédictives positives et négatives de 80 à 100% respectivement. Nous avons mis en évidence par immuno-histochimie couplée à une analyse quantitative d’images que la multiplication virale ainsi que la réponse immunitaire innée (cellules NK) et adaptative (CD8+ et plasmocytes) étaient significativement plus élevées dans les cerveaux fœtaux les plus sévèrement atteints. Ce résultat paradoxal nous a incité à quantifier la présence du marqueur PD-1 et celle de son récepteur PD-L1. PD-1 était significativement plus exprimé dans les cerveaux sévèrement atteints. L’analyse par cytométrie de flux montrait que PD-1 était exprimé par 96% des CD8+ mais aussi par plus de 70% des lymphocytes B et des cellules NK. Ces résultats témoignent de l’existence dans les cerveaux fœtaux infectés d’un épuisement immunitaire touchant la réponse adaptative mais aussi innée. Enfin, l’analyse par cytométrie de flux montrait la présence d’une réplication virale dans les différents types de cellules neuronales (cellules souches, neurones, astrocytes). En conclusion, les résultats de notre travail ont permis d’améliorer les algorithmes de prise en charge de l’infection à CMV in utero grâce à la validation de marqueurs prédictifs immuno-virologiques. Par ailleurs, le fait qu’un épuisement immunitaire et une forte multiplication virale soient associés à la sévérité de l’atteinte cérébrale est important pour l’élaboration de stratégies thérapeutiques in utero. / CMV congenital infection has a worldwide incidence estimated at about 0.7% of all life births and represents the major cause of neurological handicap of infectious origin. The management of this infection remains highly debated. Several factors contribute to this and among them are the absence of recognized prognostic markers and gaps in the knowledge of its pathogenicity particularly that of the fetal brain. The first objective of this work was to describe and validate immune and virological predictive markers of vertical transmission and of neonatal sequelae. The second objective was to study in situ immune and virological correlates of the severity of fetal brain infection. We first validated a model of materno-fetal transmission based on maternal virological results (IgG avidity and blood CMV DNA). We then showed that the viral reservoir level, estimated by the viral load in the amniotic fluid and the fetal blood, was a predictive marker of neonatal sequelae. Prognosis models combining quantification of the viral reservoir to fetal imaging allow to reach positive and negative predictive values up to 80% and 100% respectively. We showed using immunohistochemistry and quantitative image analysis that viral multiplication as well as both innate immune responses (NK cells) and adaptive immune responses (CD8+ and plasma cells) were significantly higher in the most severely infected fetal brains. This paradox drove us to quantify PD-1 and its receptor PD-L1, PD-1expression was significantly higher in severely affected fetal brains. Cytometry flow analysis evidenced that PD-1 was expressed in 95% of CD8+ cells but also in at least 70% of NK cells and of B cells. These results demonstrate immune exhaustion of both adaptive and innate responses in fetal infected brains. Finally, viral replication was evidenced in stem cells, neurons and mature astrocytes after separation by flow cytometry of these neuronal cell types. In conclusion, the validation of immune-virological markers obtained within this work has usefully improved the algorithms for the clinical management of in utero CMV infection. Moreover, the demonstration that immune exhaustion and high viral multiplication are responsible of severe fetal brain affection is important to elaborate in utero treatment strategies.

Rezidivierte und refraktäre Hodentumoren waren bis zu Beginn der 80er Jahre nur selten kurativ behandelbar. Mit Einführung der Hochdosischemotherapie in Verbindung mit autologer Stammzellreinfusion, konnte eine kurative Behandlungsoption auch in dieser prognostisch ungünstigen Situation in der Klinik etabliert werden. Die vorliegende Arbeit beschreibt die Ergebnisse der ersten Phase I/II Studie zur klinischen Etablierung dieses Therapieverfahrens ebenso wie verschiedene nachfolgende Untersuchungen zur Optimierung der Hochdosischemotherapie. Eine "matched-pair" Analyse konnte zumindest im retrospektiven Vergleich, den Nutzen dieses neuen Therapieverfahrens im Vergleich zu einer konventionell-dosierten Behandlung belegen. / Until the beginning of the 1980ies relapsed and refractory germ-cell tumors were rarely cured. With the introduction of high-dose chemotherapy in combination with autologous stem cell reinfusion, a curative treatment option could be established in this prognostically unfavorable situation. The present work describes the results from the initial phase I/II studies that established this new treatment as well as the results of several subsequent trials to optimize this new procedure. Finally, the results of a "matched-pair" analysis is presented that demonstrates the superiority of this new treatment as compared to conventional-dose chemotherapy.

INTRODUÇÃO: Embora os avanços na oncologia sejam significativos, o câncer continua sendo um desafio para a ciência médica. Neste contexto, o diagnóstico precoce assume grande relevância, visto que as ferramentas diagnósticas têm permitido o planejamento terapêutico e a definição mais precisa do prognóstico. Dentre as ferramentas mais utilizadas na Medicina Veterinária destacam-se a histopatologia e a imuno-histoquímica. O presente trabalho, além de definir a casuística das neoplasias mamárias caninas, faz uma comparação entre os resultados histopatológicos e imunohistoquímicos permitindo a definição de assinaturas morfológicas e moleculares associadas a parâmetros de pior prognóstico já definidos pela literatura. MÉTODOS: Foram analisadas 129 amostras parafinadas de carcinoma mamário em cadelas por histopatologia e imuno-histoquímica, correlacionando o perfil de expressão das proteínas COX-2, HER-2, Ki-67 e E-caderina, vimentina e p63 com os subtipos histopatológicos de neoplasias mamárias em cadelas definidos na histopatologia. RESULTADOS: Das 129 amostras 7,7% (10/129) eram não neoplásicas, 7,7% (10/129) eram benignas e 84,5% (109/129) eram malignas. O tipo de tumor mais frequente foi o carcinoma em tumor misto 26,3% (34/129). Das 109 cadelas com tumor mamário maligno, 67 (61,4%) apresentaram tumores grau I, ou de histopatologia mais favorável. Quarenta e dois cães (38,6%) tiveram tumores de grau II e III ou de pior prognóstico histológico. Os tumores de grau III apresentaram maior grau de necrose, infiltração linfocitária, invasão linfática, desmoplasia e microcalcificação que os tumores de grau I e II. Os painéis de expressão proteica revelados pela IHC evidenciaram correlação entre grau histológico e expressão de Ki-67, HER-2, COX-2, p63, vimentina e ecaderina. Considerando os tipos histológicos mais agressivos, como carcinomas sólidos e anaplásicos e carcinosarcoma, observou-se que 66% de carcinomas sólidos, 80% de carcinomas anaplásticos e 66% de carcinosarcomas apresentaram alto índice de proliferação pelo Ki67. Outros marcadores confirmaram a associação desses subtipos histológicos com outras variáveis de IHC de pior prognóstico. CONCLUSÕES: Os resultados deste estudo mostraram uma correlação entre os parâmetros histopatológicos e os marcadores imuno-histoquímicos no tumor de grau I, II e III. No entanto, alguns tumores de grau I podem apresentar um indicador de painel imuno-histoquímico de mau prognóstico e ser subestimados se apenas foram avaliados por histopatologia. Por esta razão, a definição de linhas de tratamento e o prognóstico baseados apenas na análise histopatológica é limitado e deve ser complementado por imuno-histoquímica. Além disso, uma alta prevalência de tumores malignos mamários e a semelhança de tipos histológicos e perfis de coloração imuno-histoquímica qualificam a população canina como modelo promissor para estudos de câncer translacional / INTRODUCTION: Despite significant advances in oncology, cancer remains a challenge for medical science. Early diagnosis is important in this context because the diagnostic tools have enabled therapeutic planning and more precise definition of the prognosis. Histopathology and immunohistochemistry are among the tools most used within veterinary medicine. In addition to defining a sample of cases of canine mammary neoplasia, the present study compared histopathological and immunohistochemical results and thus made it possible to define morphological and molecular signatures that were associated with parameters for worse prognoses that had already been defined in the literature. METHODS: A total of 129 paraffin-embedded mammary carcinoma samples were analyzed histopathologically and immunohistochemically. The expression profiles of the proteins COX-2, HER-2, Ki-67, E-cadherin, vimentin and p63 were correlated with the histopathological subtypes of breast neoplasms in female dogs that were defined. RESULTS: Out of the 129 samples, 7.7% (10/129) were non-neoplastic, 7.7% (10/129) were benign and 84.5% (109/129) were malignant. The most frequent tumor type was mixed-tumor carcinoma, in 26.3% (34/129). Among the 109 female dogs with malignant mammary tumors, 67 (61.4%) presented grade I tumors, or more favorable histopathology. Forty-two (38.6%) had grade II and III tumors or worse histological prognosis. Grade III tumors had higher degrees of necrosis, lymphocytic infiltration, lymphatic invasion, desmoplasia and microcalcification than did grade I and II tumors. The protein expression panels revealed through immunohistochemical analysis showed correlations between histological grade and expression of Ki-67, HER-2, COX-2, p63, vimentin and ecadherin. Among the more aggressive histological types such as solid and anaplastic carcinomas and carcinosarcoma, it was observed that 66% of solid carcinomas, 80% of anaplastic carcinomas and 66% of carcinosarcomas presented high proliferation rates, shown by Ki67. Other markers confirmed the association of these histological subtypes with other immunohistochemical variables for worse prognosis. CONCLUSIONS: The results from this study showed correlations between the histopathological parameters and the immunohistochemical markers in tumors of grades I, II and III. However, it was seen that some grade I tumors with immunohistochemical panels indicating poor prognosis could be underestimated if they were only evaluated by histopathology. For this reason, definition of treatments and prognoses based only on histopathological analysis is limited and should be complemented by immunohistochemistry. In addition, the high prevalence of malignant mammary tumors and the similarity of histological types and immunohistochemical staining profiles qualify the canine population as a promising model for translational cancer studies

O carcinoma epidermoide bucal (CEB) é uma malignidade epitelial que causa grande mortalidade. As metalotioneínas (MTs) são proteínas envolvidas na homeostasia de metais e eventos oxidativos. Estudos de expressão proteica a apontaram como marcadora de prognóstico e comportamento metastático para o CEB. A análise da expressão gênica das mesmas tem auxiliado no entendimento deste papel para outros tumores, mas ainda não foi estudada no CEB. O objetivo deste trabalho foi avaliar o perfil de expressão gênica das MTs no CEB e em fragmentos de mucosa oral (MOC), além de sua relação com dados clínicopatológicos, comportamento metastático e prognóstico. Para tal, foram utilizadas amostras armazenadas a -80º C no Banco Nacional de Tumores do Instituto Nacional de Câncer, constando de 35 casos de CEB de língua e/ou assoalho bucal e 35 MOC. Todos os fragmentos foram submetidos ao qRT-PCR com uso de TaqMan® para os genes: MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1X, MT2A, MT3 e MT4. A expressão dos genes MT1B e MT1H foi raramente detectada. Houve queda significativa de expressão dos genes MT1A, MT1X, MT3 e MT4 e aumento significativo de expressão de MT1F no CEB com relação à MOC. Casos de baixa expressão de MT1G tiveram pior prognóstico. A alta expressão de MT1X indicou casos não metastáticos e a alta expressão de MT3 indicou casos metastáticos. Em suma, foi demonstrado pela primeira vez o perfil gênico das MTs no CEB, indicando que a mesma pode fornecer informações sobre o prognóstico e comportamento metastático do CEB. / The oral squamous cell carcinoma (OSCC) is a malignancy that causes high mortality. Metallothioneins (MTs) are proteins involved in metal homeostasis and antioxidant events. Studies regarding its protein expression indicated its potential as marker of prognosis and metastatic behavior, also for OSCC. The analysis of its specific gene expression can clarify its importance in these aspects and no study has been done for OSCC. The aim of this work was to evaluate the profile of gene expression of MTs in OSCC and samples of non-neoplastic oral mucosa (OM), evaluating its relationship with clinic-pathologic characteristic, metastatic behavior and prognosis for OSCC. For this, tissue samples archived at -80º C at the National Bank of Tumors of the Brazilian National Institute of Cancer were collected, in a total of 35 cases of OSCC and 35 fragments of OM. All tissues were submitted to qRTPCR with TaqMan® for the genes: MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1X, MT2A, MT3 e MT4, besides the constitutive gene GAPDH. Expressions of MT1B and MT1H were rarely detected. There was significant loss of expression for MT1A, MT1X, MT3 and MT4 and gain of expression for MT1F comparing OSCC with OM. Cases with down-regulation of MT1G had the worst prognosis. Up-regulation of MT1X indicated non-metastatic cases whereas up-regulation of MT3 indicated metastatic ones. In conclusion, this study shows for the first time the profile of gene expression of MTs on OSCC indicating distinctive patterns of regulation for each, and giving associations with prognosis and metastatic behavior of cases.

Os gliomas são tumores do sistema nervoso central (SNC) que evoluem a partir das células da glia. O tipo mais frequente e mais agressivo destes tumores é conhecido como glioblastoma multiforme (GBM) e entre as características biológicas de agressividade associadas a esse tumor estão o seu rápido crescimento e ausência de apoptose. O seu prognóstico desfavorável está associado à dificuldade de tratamento dessas células, pois possuem resistência à quimioterapia e a radioterapia. A expressão gênica das enzimas ciclooxigenase-1 (COX-1), ciclooxigenase-2 (COX-2), prostaglandina E sintase-1 microssomal (mPGES-1), prostaglandina E sintase-2 microssomal (mPGES-2), prostaglandina E sintase citosólica (cPGES) e os produtos da síntese destas enzimas, incluindo a prostaglandina E1 (PGE1) e a prostaglandina E2 (PGE2) estão diretamente relacionados com a malignidade dos gliomas. A PGE1 e a PGE2 podem atuar de modo autócrino e parácrino, interagindo com suas células alvos através de ligação aos receptores da superfície celular que estão ligados a proteína G. Estes receptores são conhecidos como receptores EPs e dividem-se em quatro subtipos: EP-1, EP-2, EP-3 e EP-4 sendo que cada um deles ativa vias distintas de sinalização intracelular. Desta forma, este estudo teve por objetivo analisar in vitro o papel da PGE1, PGE2 e seus receptores na proliferação e apoptose em glioma humano, e a expressão das enzimas COX-1, COX-2, mPGES-1, mPGES-2 e cPGES. / Gliomas are tumors of the central nervous system (CNS) that evolve from glial cells. The most common and most aggressive form of these tumors is known as glioblastoma multiforme (GBM). The biological aggressiveness of GBM is associated with its rapid growth and lack of apoptosis. Its poor prognosis is strongly associated with the difficulty of treating these cells as they are resistant to chemotherapy and radiotherapy. The gene expression of the enzymes cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), microsomal prostaglandin E synthase-2 (mPGES-2), cytosolic prostaglandin E synthase (cPGES) and the products of the activity of these enzymes, including prostaglandin E1 (PGE1) and prostaglandin E2 (PGE2), are directly related to the malignancy of gliomas. PGE1 and PGE2 can act in an autocrine and paracrine manner, by interacting with their target cells via binding to cell surface receptors that are linked to G-proteins. These receptors are known as EP receptors and are divided into four subtypes: EP1, EP2, EP3 and EP4; each of which activates distinct intracellular signaling pathways. Therefore, this study aimed to analyze, in vitro, the role of PGE1, PGE2 and their receptors in the proliferation and apoptosis of human glioma and the expression of COX-1, COX-2, mPGES-1, mPGES-2 and cPGES.

Estudou-se fatores associados a refratariedade do Transtorno Obsessivo-Compulsivo aos tratamentos convencionais em 23 pacientes refratários e 26 respondedores. Os refratários mostraram: sintomas obsessivo-compulsivos, depressivos e ansiosos mais intensos; pior qualidade de vida; mais freqüentemente não ter cônjuge, ter menor escolaridade e condição sócio-econômica, maior acomodação familiar, curso crônico da doença, maior freqüência de conteúdo sexual/religioso, maior período de tempo para iniciar o tratamento e Transtorno Alimentar co-mórbido. O modelo de regressão logística mostrou que maior acomodação familiar e sintomas sexuais/religiosos estão associadas à refratariedade. / We studied possible associated factors of conventional treatment refractoriness in 23 refractory versus 26 respondent Obsessive Compulsive Disorder patients. Refractories had: higher severity of OC, depression and anxiety symptoms; worse quality of life; no spouse; less scholarship; lower social class; higher family accommodation; chronic course of the disease; more frequent sexual/religious symptoms; a longer period to begin the treatment; and comorbid Eating Disorder. Regression analysis model showed that, higher family accommodation and sexual/religious symptoms are associated to refractoriness

Sepse é causa comum de óbito, e vários fatores prognósticos têm sido identificados. Entretanto, é possível que a rota do paciente séptico no hospital também tenha efeito sobre o prognóstico. Nosso objetivo foi verificar se a rota do paciente séptico antes da admissão na UTI tem efeito sobre a letalidade hospitalar. Métodos Foi realizado um estudo de coorte retrospectiva com 489 pacientes com sepse grave ou choque séptico (idade >=18 anos), internados na Unidade de Terapia Intensiva. Analisamos se a rota está associada a mortalidade hospitalar usando modelo de regressão de Cox com variância robusta. Resultados Dos 489 pacientes, 207 (42,3%) foram diagnosticados com sepse na Unidade de Pronto Atendimento (UPA), 185 (37,8%) em unidade de internação clínica ou cirúrgica (Clínica Médica Cirúrgica - CMC), 56 (13,3%) em Unidade Semi-Intensiva (USI) e 32 (6,5%) em Unidade Terapia Intensiva.(UTI). A maioria (56,6%) dos pacientes era do sexo masculino, a idade média foi de 66,3 anos, 39,8% tinham APACHE II de 25 ou mais, e 77,5% tinham o diagnóstico de choque séptico. A letalidade foi 41,9%. Na análise multivariada com ajuste para diversos fatores prognósticos, incluindo tempo de internação hospitalar antes da admissão na UTI, não houve diferença estatisticamente significativa no risco de óbito entre pacientes com sepse grave diagnosticada na UPA ou CMC (risco relativo [RR] 1,36; intervalo de confiança [IC] 95% 1,00 a 1,83). Porém, o risco de óbito hospitalar foi maior nos pacientes em que a sepse grave foi diagnosticada na USI ou UTI (RR 1,64; IC 95% 1,20 a 2,25). Conclusão A mortalidade dos pacientes com sepse grave ou choque séptico atendidos na CMC é similar à de pacientes com sepse diagnosticada na UPA. Entretanto, o risco de óbito hospitalar foi maior nos pacientes que desenvolveram sepse na USI ou UTI / Sepsis is a common cause of death. Several predictors of hospital mortality have been identified. However, it is possible that the route the septic patient takes within the hospital may also affect endpoints. Thus, our main objective was to verify whether the routes of septic patients before being admitted to ICU affect their in-hospital mortality. Methods Retrospective cohort study of 489 patients with severe sepsis or septic shock (age >= 18 years) admitted to the Intensive Care Unit. We analyzed the impact of route on in-hospital mortality using Cox regression with robust variance. Results Of 489 patients, 207 (42.3%) presented with severe sepsis in the ED, 185 (37.8%) were diagnosed with severe sepsis in the ward, 56 (13.3%) in the step down unit and 32 (6.5%) in the ICU. The mortality rate was 41.9%. The mean age was 66.3 years, and 56.6% were men. APACHE II scores were >25 in 39.8% of patients, and 77.5% were diagnosed with septic shock. In the multivariate analysis, with adjustment for several prognostic factors including length of hospital stay before ICU admission, there was no statistically significant difference in the risk of death between patients who had severe sepsis diagnosed in the ED compared to CMC (relative risk [RR] 1,36; IC 95% 1,00 a 1,83). However, the risk of death was increased in patients who had severe sepsis diagnosed in the step-down unit or ICU (RR 1,64; IC 95% 1,20 a 2,25). Conclusion Patients who have severe sepsis or septic shock diagnosed in the CMC have in-hospital mortality similar to those who present with severe sepsis or septic shock in the ED. However, patients who develop severe sepsis in the step-down unit or ICU have higher mortality