Real-world molecular testing and treatment patterns in brazilian patients with newly diagnosed locally advanced or metastatic NSCLC

OBJECTIVES: To evaluate the molecular testing and treatment patterns in a retrospective cohort of newly diagnosed treatment-naïve patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: This is an observational retrospective cohort study conducted across 10 cancer centers in Brazil. Treatment-naïve patients with locally advanced or metastatic NSCLC were enrolled from January to December 2014. The following data were collected from the medical records of patients from diagnosis until the last record (death, loss to follow-up, or the end of the maximum follow-up period): demographics; medical history; smoking status; disease characteristics; previous treatments; and molecular testing patterns and results. The overall survival (OS) was also estimated. Results: A total of 391 patients from 8 different Brazilian states were included, with a median age of 64.1 years (23.7-98.7), with most patients being males (60.1%). The smoking status of 74.2% of patients was a 'former' or 'current smoker'. Stage IV NSCLC at diagnosis was observed in 82.4% of patients, with 269 of them (68.8%) presenting adenocarcinoma (ADC). Among the stage IV ADC patients, 54.0% were referred for molecular testing. Among the patients with an available epidermal growth factor receptor (EGFR) mutation status, 31 (24.0%) were EGFR-positive. The first-line treatment was a platinum-based chemotherapy for 98 patients (25.1%), while non-platinum-based regimens were used in 54 patients (13.8%). OS data were available for 370 patients, with a median OS of 10.8 months. Never smokers had a significantly higher median OS versus current or former smokers (14.6 versus 9.1 months; log-rank p=0.003). Among the patients for whom molecular testing data were available, those with EGFR-positive results had a longer median OS (34.6 versus 12.8 months; log-rank p=0.003). Conclusion: Our findings provide relevant information for prescribers and policy decision-makers by highlighting the unmet needs of patients and the importance of molecular testing in newly diagnosed locally advanced or metastatic lung adenocarcinoma. We also highlight the respective EGFR-tyrosine kinase inhibitor treatment when the result is positive and the areas in which further efforts are required to grant access to effective treatment.

Avaliação da expressão de TollLike Receptors (TLR), e fatores de transcrição MPKp38 e NFBp65 em pacientes com carcinoma escamoso de pênis / Evaluation of expression TollLike Receptors (TLR) and transcription factor p38 and MPK NFκBp65 in patients with squamous cell carcinoma of the penis

Introdução: A modulação do processo inflamatório por TLRs pode ser um fator chave no desenvolvimento e progressão tumoral, induzindo tanto a respostas pró-tumorais, como anti-tumorais, muitas vezes através da regulação da sinalização pela NF-B e subsequente produção de fatores de crescimento e proteínas anti-apoptóticas. A magnitude e duração da ativação dos TLRs são fundamentais para o desenvolvimento de um estado inflamatório pró-tumoral ou resposta anti-tumoral. O conhecimento de suas vias pode influenciar na aplicação clínica dos imunoterápicos como tratamento do carcinoma escamoso de pênis. Consequentemente, decidimos investigar a expressão de receptores TLR e fatores de transcrição em pacientes com câncer de pênis, ainda não descrito na literatura. Objetivos: Avaliar a expressão dos receptores Toll-like 2 e 9, e das vias de sinalização intracelular NF-Bp65 e MAPKp38 no carcinoma escamoso de pênis. Métodos: Foram incluídos um total de 38 pacientes masculinos com câncer de pênis, com idade ≥ 18 anos. Como grupo controle, foram incluídos 15 homens saudáveis. A concentração sérica de proteínas foi determinada pela técnica de citometria de fluxo. Para análises estatísticas, foram utilizados os testes de Mann-Whitney e de correlação de Spearman. Foi considerado significativo p < 0,05. Resultados: Em sangue periférico, houve uma maior quantidade de leucócitos com expressão de TLR2 e MAPKp38 em pacientes, compardo aos controles saudáveis (p=0,002 e p<0,0001, respectivamente), enquanto os leucócitos que expressavam TLR9 e NFkB foram mais numeroso em controles saudáveis (p=0,03 e p=0,03, respectivamente). Em neutrófilos, havia um maior número com expressão de NFBp65 e MAPKp38, em controles (p=0,001 e p<0,0001, respectivamente). Já nos monócitos, havia o maior número de células com expressão de TLR9 e MAPKp38, em pacientes com câncer de pênis (p=0,003 e p=0,01, respectivamente). Nos pacientes com tumores > 3,5 cm, há um maior número de leucócitos totais que expressam TLR9, NFBp65 e MAPKp38 (p=0,01; p=0,008 e p=0,03, respectivamente), uma maior quantidade de neutrófilos com expressão de TLR2 e NFBp65 (p=0,0008 e p=0,01, respectivamente). Já em tumores ≤ 3,5 cm, uma maior quantidade de monócitos expressavam NFBp65 (p=0,02). Não houve diferença em leucócitos totais, na expressão dos receptores ou fatores de transcrição na avaliação de IPN (Invasão perineural), porém em pacientes com IPN+, havia um maior número de monócitos e neutrófilos com expressão de TLR9 (p=0,009 e p=0,0003, respectivamente). No tecido tumoral, houve uma maior expressão de TLR9 e NFBp65 em pacientes com tumores ≤ 3,5cm (p= 0,02). Não foi observado correlação entre níveis de TLR2, TLR9 e NFBp65 entre tecido tumoral e sangue periférico. No tecido tumoral, havia uma correlação positiva moderada entre TLR2 e TLR9 (r=0.65, p=0.0009) e TLR9 e NFBp65 (r=0.60; p=0.003), além de correlação positiva alta entre TLR2 e NFBp65 (r=0.78; p<0.0001). Conclusão: Existem alterações nos níveis sanguíneos de TLR2, TLR9, NFBp65 e MAPKp38, em diferentes níveis, a depender do tipo celular, e em tecido tumoral que podem funcionar como fatores prognósticos e preditivos de tratamento para pacientes com CEC de pênis

Introduction: Modulation of the inflammatory process by TLRs may be a key factor in tumor development and progression, inducing both pro-tumor and anti-tumor responses, often through the regulation of NF-κB signaling and subsequent growth factor and anti-apoptotic proteins production. The magnitude and duration of TLR activation are critical for the development of a pro-tumor inflammatory state or anti-tumor response. Knowledge of its pathways may influence the clinical application of immunotherapeutics as a treatment for squamous cell carcinoma of the penis. Consequently, we decided to investigate the expression of TLR receptors and transcription factors in patients with penile cancer, not yet described in the literature. Objectives: To evaluate the expression of Toll-like receptors 2 and 9, and the intracellular signaling pathways NF-κBp65 and MAPKp38 in squamous cell carcinoma of the penis. Methods: A total of 38 male patients with penile cancer, aged ≥ 18 years, were included. As a control group, 15 healthy men were included. Serum protein concentration was determined by the flow cytometry technique. For statistical analysis, the Mann-Whitney tests, and Spearman's correlation were used. It was considered significant p <0.05. Results: In peripheral blood, there were more leukocytes expressing TLR2 and MAPKp38 in patients, compared to healthy controls (p = 0.002 and p <0.0001, respectively), whereas leukocytes expressing TLR9 and NFκB were more numerous in healthy controls (p = 0.03 and p = 0.03, respectively). In neutrophils, there was a greater number with expression of NFκBp65 and MAPKp38, in controls (p = 0.001 and p <0.0001, respectively). In monocytes, there were the highest number of cells expressing TLR9 and MAPKp38 in patients with penile cancer (p = 0.003 and p = 0.01, respectively). In patients with tumors> 3.5 cm, there is a greater number of total leukocytes expressing TLR9, NFκBp65 and MAPKp38 (p = 0.01, p = 0.008 and p = 0.03, respectively), a higher amount of neutrophils with expression of TLR2 and NFκBp65 (p = 0.0008 and p = 0.01, respectively). Already in tumors ≤ 3.5 cm, a higher amount of monocytes expressed NFκBp65 (p = 0.02). There was no difference in total leukocytes, expression of the receptors or transcription factors in the IPN assessment, but in patients with IPN +, there was a higher number of monocytes and neutrophils with TLR9 expression (p = 0.009 and p = 0.0003, respectively) . In tumor tissue, there was a greater expression of TLR9 and NFκBp65 in patients with tumors ≤ 3.5 cm (p = 0.02). No correlation was found between levels of TLR2, TLR9 and NFκBp65 between tumor tissue and peripheral blood. In the tumor tissue, there was a moderate positive correlation between TLR2 and TLR9 (r = 0.65, p = 0.0009) and TLR9 and NFκBp65 (r = 0.60; p = 0.003), and a high positive correlation between TLR2 and NFκBp65 (r = 0.78; p <0.0001). Conclusion: There are changes in blood levels of TLR2, TLR9, NFκBp65 and MAPKp38, at different levels, depending on the cell type, and on tumor tissue that may function as prognostic and predictive factors of treatment for patients with penile SCC

Frequency of and risk factors associated to Leptospira spp. Seropositivity in goats in the state of Sergipe, Northeastern Brazil / Frequência e fatores de riscos associados a caprinos soropositivos a Leptospiras spp. no Estado de Sergipe, Nordeste do Brasil

ABSTRACT: The objective of this study was to determine the frequency and factors associated with the occurrence of seropositivity for Leptospira spp. in goat herds in the state of Sergipe, Brazil, on the basis of the analysis of 675 samples collected from 41 properties in 2013-2014. Analysis of anti-Leptospira spp. antibodies revealed that 25.74% goats (194) were seropositive and that 90.24% (37) of the properties had at least one infected goat. The most prevalent serogroup was Icterohaemorrhagiae (85.57%); although, the study animals were reactive to other serogroups: Australis (5.15%), Pomona (3.61%), Sejroe (3.09%), and Pyrogenes (2.58%) had titers ≤400 in 96.91% of cases. The origin of the water source [still water source (OR=3.86)] was associated with seropositivity. Results reflected the importance of adopting appropriate management practices for herds in Sergipe.

RESUMO: O objetivo deste estudo foi determinar a frequência e os fatores associados à soropositividade para Leptospira spp. em caprinos do Estado de Sergipe, Nordeste do Brasil, utilizando 675 animais de 41 propriedades no período de 2013 e 2014. A frequência de positividade entre os animais foi de 25,74% (194), e em 90,24% (37) das propriedades houve pelo menos um animal soropositivo. O sorogrupo reagente predominante foi o Icterohaemorrhagiae (85,57%), com presença também de animais reagentes para Australis (5,15%), Pomona (3,61%), Sejroe (3,09%) e Pyrogenes (2,58%) com títulos ≤400 em 96,91% dos casos. A origem da água fornecida (água parada) (OR=3,86) foi o fator associado à presença de caprinos positivos. Ressalta-se a importância da adoção de práticas de manejo adequadas nos rebanhos caprinos sergipanos.

Does the evaluation of coagulation factors contribute to etiological diagnosis of pleural effusions?

OBJECTIVE: The aim of this study was to identify the participation of the coagulation system in the differential diagnosis of pleural effusions. INTRODUCTION: Imbalance between immunologic and metabolic factors triggers a sequence of events resulting in pleural reactions and accumulation of fluid. The coagulation system, which is fundamental for the maintenance of homeostasis, contributes to the inflammatory process responsible for pleural effusions, and participates in cellular proliferation and migration as well as in the synthesis of inflammatory mediators. METHODS: We evaluated the laboratory profile of coagulation and fibrinolysis in 54 pleural fluids (15 transudates and 39 exudates). RESULTS: The coagulation system acts according to the pathophysiologic mechanisms involved in the development of pleural effusions. In inflammatory effusions (exudates), there is activation of coagulation with increased levels of fragment 1+2 and thrombin-antithrombin complex in addition to reduction of fibrinogen levels due to fibrinolysis and fibrin tissue incorporation. As a consequence, there is activation of the fibrinolytic system with increased levels of fibrin degradation products, including the D-dimer. These changes are not sufficient for differentiation of different subgroups of exudates. In transudates, these events were observed to a lesser degree. CONCLUSION: The coagulation system plays an important role in the development of pleural diseases. Coagulation tests show differences between transudates and exudates but not among exudate subgroups. Understanding the physiopathological mechanisms of pleural disorders may help to define new diagnostic and therapeutic approaches.

Hipercoagulabilidade e câncer de pulmão: [revisão] / Hypercoagulability and lung cancer: [review]

A relação entre câncer e alteração na coagulação já havia sido sugerida há quase 150 anos por Trousseau e, subseqüentemente, ficou claro o maior risco que os pacientes oncológicos têm de desenvolverem fenômenos tromboembólicos. Isto pode ser conseqüência da ativação do sistema de coagulação pelas células neoplásicas ou pelas terapias empregadas (quimioterapias e cirurgias). Tais fenômenos podem, ainda, ser a primeira manifestação do câncer e a sua recorrência, mesmo com anticoagulação adequada, foi descrita. O sistema de coagulação é ativado, normalmente, com finalidade reparativa. Na presença de neoplasias, este complexo sistema está atuante frente a variados estímulos e parece contribuir para a progressão tumoral. Este efeito é mais importante para os focos metastáticos que para o próprio tumor primário. Contudo, a maior parte das vítimas de neoplasias morre das complicações das metástases, revelando a importância deste tema. Nesta área, vários mecanismos já são conhecidos e geram interessantes perspectivas para tratamentos futuros. Atualmente, o sucesso obtido com as heparinas de baixo peso molecular no carcinoma de pequenas células de pulmão é animador. Embora o conhecimento sobre esses mecanismos sejam relativamente recentes, os campos de pesquisa e tratamento estão amplamente abertos.

The relationship between cancer and coagulopathy was suggested by Trousseau nearly 150 years ago. Later, it became more evident that oncologic patients are at a higher risk of experiencing thromboembolic events. This can be due to activation of the coagulation system either by neoplastic cells or by prescribed therapies (chemotherapy or surgical procedures). In fact, these events can constitute the first manifestation of cancer, and their recurrence, despite efficient anticoagulation, has been described. The coagulation system is normally activated in order to provide healing. In the presence of neoplasms, this complex system is activated as a response to multiple stimuli and seems to contribute to cancer progression. Activation of the coagulation system has a greater effect on metastatic foci than on the primary tumor. However, most cancer victims die from complications caused by metastasis, which underscores the importance of this theme. In this area, various mechanisms have been described, creating promising perspectives for future treatments. The current success in using low-molecular-weight heparins against small cell lung cancer is encouraging. Although the knowledge of those mechanisms is relatively incipient, many basic research and clinical studies are underway.

Tumor estromal de jejuno como causa de sangramento: relato de caso / Stromal tumor of the small bowel causing hemorrhage: a case report

As neoplasias do intestino delgado são inco¡muns. Os tumores do estroma gastrointestinal (GISTs) são tumores mesenquimais específicos do trato gastrointestinal e abdome e correspondem a um grupo de tumores mesenquimais c-KIT po¡sitivos. Relata-se caso de GIST no jejuno de cres¡cimento extraluminal, apresentando-se com san¡gramento digestivo de repetição, diagnosticado apenas através de laparotomia, após propedêu¡tica não elucidativa. A paciente submeteu-se a enterectomia, sem intercorrências no pós-opera¡tório. Os exames histopatológico e de imunohis¡toquímica confirmaram o diagnóstico.