Functional and genomic characterization of three novel cell lines derived from a metastatic gallbladder cancer tumor

BACKGROUND: Gallbladder cancer (GBC) is the most common tumor of the biliary tract. The incidence of GBC shows a large geographic variability, being particularly frequent in Native American populations. In Chile, GBC represents the second cause of cancer-related death among women. We describe here the establishment of three novel cell lines derived from the ascitic fluid of a Chilean GBC patient, who presented 46% European, 36% Mapuche, 12% Aymara and 6% African ancestry. RESULTS: After immunocytochemical staining of the primary cell culture, we isolated and comprehensively characterized three independent clones (PUC-GBC1, PUC-GBC2 and PUC-GBC3) by short tandem repeat DNA profiling and RNA sequencing as well as karyotype, doubling time, chemosensitivity, in vitro migration capability and in vivo tumorigenicity assay. Primary culture cells showed high expression of CK7, CK19, CA 19-9, MUC1 and MUC16, and negative expression of mesothelial markers. The three isolated clones displayed an epithelial phenotype and an abnormal structure and number of chromosomes. RNA sequencing confirmed the increased expression of cytokeratin and mucin genes, and also of TP53 and ERBB2 with some differences among the three cells lines, and revealed a novel exonic mutation in NF1. The PUC-GBC3 clone was the most aggressive according to histopathological features and the tumorigenic capacity in NSG mice. CONCLUSIONS: The first cell lines established from a Chilean GBC patient represent a new model for studying GBC in patients of Native American descent.

Construction of Mycobacterium tuberculosis cdd knockout and evaluation of invasion and growth in macrophages

Cytidine deaminase (MtCDA), encoded by cdd gene (Rv3315c), is the only enzyme identified in nucleotide biosynthesis pathway of Mycobacterium tuberculosis that is able to recycle cytidine and deoxycytidine. An M. tuberculosis knockout strain for cdd gene was obtained by allelic replacement. Evaluation of mRNA expression validated cdd deletion and showed the absence of polar effect. MudPIT LC-MS/MS data indicated thymidine phosphorylase expression was decreased in knockout and complemented strains. The cdd disruption does not affect M. tuberculosis growth both in Mid- dlebrook 7H9 and in RAW 264.7 cells, which indicates that cdd is not important for macrophage invasion and virulence.

Establishment of patient-derived tumor xenograft (PDTX) models using samples from CT-guided percutaneous biopsy

This study aimed to investigate the feasibility of the establishment of a human cancer xenograft model using samples from computed tomography (CT)-guided percutaneous biopsy. Fresh tumor tissues obtained from 10 cancer patients by CT-guided percutaneous biopsy were subcutaneously inoculated into NOD-Prkdcem26Il2rgem26Nju (NCG) mice to establish human patient-derived tumor xenograft (PDTX) models. The formation of first and second generation xenografts was observed, and tumor volume was recorded over time. Tumor tissue consistency between the PDTX model and primary tumors in patients was compared using H&E staining and immunohistochemistry. Pharmacodynamic tests of clinically used chemotherapeutic drugs were conducted on second generation xenografts, and their effects on tumor growth and body weight were observed. CT-guided percutaneous biopsy samples were successfully collected from 10 patients with advanced cancers. The PDTX model was established in mice using tumor samples obtained from 4 cancer patients, including one small cell carcinoma sample, two adenocarcinoma samples, and one squamous cell carcinoma sample. The success rate was 40%. The obtained PDTX model maintained a degree of differentiation, and morphological and structural characteristics were similar to primary tumors. The pharmacodynamic test of chemotherapeutic drugs in the PDTX model revealed a therapeutic effect on tumor growth, as expected. CT-guided percutaneous biopsy samples can be effectively used to establish a PDTX model, and test these chemotherapy regimens.

Recomendaciones sobre el manejo del cáncer de páncreas tipo adenocarcinoma en Latinoamérica: Reunión del Consenso del Simposio Latinoamericano de Gastroenterología Oncológica (SLAGO) y de la Asociación Ibero Latinoamericana de Terapia Radiante (ALATRO), Viña del Mar, Chile 2015 / Recommendations for the management of pancreatic cancer type adenocarcinoma: A consensus statement reached during the 2015 Latin American Symposium on Gastroenterological Oncology

Pancreatic cancer is a malignancy of great impact in developed countries and is having an increasing impact in Latin America. Incidence and mortality rates are similar for this cancer. This is an important reason to offer to the patients the best treatments available. During the Latin American Symposium of Gastroenterology Oncology (SLAGO) held in Viña del Mar, Chile, in April 2015, a multidisciplinary group of specialists in the field met to discuss about this disease. The main conclusions of this meeting, where practitioners from most of Latin American countries participated, are listed in this consensus that seek to serve as a guide for better decision making for patients with pancreatic cancer in Latin America.

Síndrome hemolítico-urêmica causada por gencitabina em uma paciente jovem com colangiocarcinoma / Hemolytic uremic syndrome due to gemcitabine in a young woman with cholangiocarcinoma

Resumo A gencitabina é um fármaco utilizado no tratamento de vários tipos de neoplasias malignas. Há poucas descrições de associação entre a droga e a síndrome hemolítico-urêmica (SHU), apesar de os pacientes em questão terem ido a óbito em pelo menos 50% dos casos. O presente artigo relata o caso de uma paciente com 25 anos de idade em remissão diagnosticada com colangiocarcinoma que apresentou anemia hemolítica microangiopática acompanhada de insuficiência renal aguda anúrica após cinco ciclos de quimioterapia com gencitabina; as manifestações eram condizentes com SHU causada pelos efeitos colaterais do medicamento. A administração de gencitabina foi interrompida, e a paciente foi tratada com hemodiálise, transfusões de sangue, trocas de plasma, corticosteroides, doxiciclina e rituximabe. Foi atingido um desfecho favorável; mais especificamente, a hemólise foi controlada e a função renal foi plenamente restabelecida.

Abstract Gemcitabine is a medication used to treat various types of malignant neoplasms. Its association with hemolytic uremic syndrome (HUS) has been described in few cases, although these cases have resulted in mortality rates of at least 50%. We report on the case of a 25-year-old patient with cholangiocarcinoma in remission who developed microangiopathic hemolytic anemia with acute anuric renal failure after receiving 5 cycles of gemcitabine chemotherapy; this condition was consistent with HUS caused by the side effects of this drug. The administration of gemcitabine was stopped, and hemodialysis, blood transfusions, plasma exchanges, steroids, doxycycline, and rituximab were used to treat the patient. A favorable outcome was achieved; in particular, hemolysis was controlled, and renal function was completely recovered.

Apoio social à mulher mastectomizada: um estudo de revisão / Social support to women after mastectomy: a review study

Para fundamentar as ações de cuidado integralizado em saúde da mulher é necessário compreender de que modo o apoio social pode contribuir para minimizar as repercussões do diagnóstico e do tratamento da neoplasia mamária. O objetivo deste estudo é analisar a contribuição da produção científica nacional e internacional acerca do apoio social percebido por mulheres diagnosticadas com câncer de mama. A amostra foi constituída de 12 publicações, obtidas a partir de critérios de inclusão preestabelecidos, nas bases de dados MedLine, Lilacs e PsycINFO, na última década (2000-2010). Os resultados foram sistematizados em categorias temáticas: percepção do apoio familiar, apoio social percebido, percepção do apoio educacional, necessidade de aprimoramento da pesquisa e assistência às mastectomizadas e suas famílias. Os estudos dedicados à dimensão subjetiva do apoio social ainda são incipientes. As evidências disponíveis sugerem que a literatura é circunscrita a temas de interesse das profissões tradicionais da área da saúde, como Enfermagem e Medicina, privilegiando construtos que podem ser diretamente quantificados. A preocupação com o apoio social deve estar presente desde a fase de diagnóstico até a reabilitação psicossocial, como parte do processo de enfrentamento.

It is necessary to understand how social support can contribute to minimize the impact of the diagnosis and treatment of mammary tumors in order to underpin the actions of comprehensive women's health care. This study seeks to analyze the contribution of the national and international literature regarding the perceived social support by women diagnosed with breast cancer. Twelve studies were selected from the MedLine, Lilacs and PsycINFO databases over a 10-year period (2000-2010) with pre-defined criteria for inclusion. The results were organized into thematic categories: the perception of family support; perceived social support; the perception of educational support; the need to improve the research and the assistance given to women after mastectomy and their families. The studies dedicated to the subjective dimension of social support are still incipient. The available evidence suggests that the literature is limited to topics of interest to the traditional health professions, such as Nursing and Medicine, focusing on constructs that can be directly quantified. The concern with social support must be present from the time of diagnosis to psychosocial rehabilitation, as part of the process of tackling the situation.

Therapeutic switching: from antidermatophytic essential oils to new leishmanicidal products

This study examined whether the antidermatophytic activity of essential oils (EOs) can be used as an indicator for the discovery of active natural products against Leishmania amazonensis. The aerial parts of seven plants were hydrodistilled. Using broth microdilution techniques, the obtained EOs were tested against three strains of dermatophytes (Trichophyton mentagrophytes, Microsporum gypseum and Microsporum canis). To compare the EOs antifungal and antiparasitic effects, the EOs activities against axenic amastigotes of L. amazonensis were concurrently evaluated. For the most promising EOs, their antileishmanial activities against parasites infecting peritoneal macrophages of BALB/c mice were measured. The most interesting antifungal candidates were the EOs from Cymbopogon citratus, Otacanthus azureus and Protium heptaphyllum, whereas O. azureus, Piper hispidum and P. heptaphyllum EOs exhibited the lowest 50% inhibitory concentration (IC50) values against axenic amastigotes, thus revealing a certain correspondence between both activities. The P. hispidum EO was identified as the most promising product in the results from the infected macrophages model (IC50: 4.7 µg/mL, safety index: 8). The most abundant compounds found in this EO were sesquiterpenes, notably curzerene and furanodiene. Eventually, the evaluation of the antidermatophytic activity of EOs appears to be an efficient method for identifying new potential drugs for the treatment of L. amazonensis.

Waiting times for surgical and diagnostic procedures in public hospitals in Mexico / Tiempos de espera para procedimientos quirúrgicos y diagnósticos en hospitales públicos de México

Objective. A retrospective evaluation of waiting times for elective procedures was conducted in a sample of Mexican public hospitals from the following institutions: the Mexican Institute for Social Security (IMSS), the Institute for Social Security and Social Services for Civil Servants (ISSSTE) and the Ministry of Health (MoH). Our aim was to describe current waiting times and identify opportunities to redistribute service demand among public institutions. Materials and methods. We examined current waiting times and productivity for seven elective surgical and four diagnostic imaging procedures, selected on the basis of their relative frequency and comparability with other national health systems. Results. Mean waiting time for the seven surgical procedures in the three institutions was 14 weeks. IMSS and ISSSTE hospitals showed better performance (12 and 13 weeks) than the MoH hospitals (15 weeks). Mean waiting time for the four diagnostic procedures was 11 weeks. IMSS hospitals (10 weeks) showed better average waiting times than ISSSTE (12 weeks) and MoH hospitals (11 weeks). Conclusion. Substantial variations were revealed, not only among institutions but also within the same institution. These variations need to be addressed in order to improve patient satisfaction.

Objetivo. Se llevó a cabo una evaluación retrospectiva de los tiempos de espera para procedimientos electivos en una muestra de hospitales públicos en México de las siguientes instituciones: Instituto Mexicano del Seguro Social (IMSS), Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE) y Secretaría de Salud (SS). El propósito era describir la situación actual en materia de tiempos de espera e identificar oportunidades de redistribución de la demanda de servicios entre instituciones públicas. Material y métodos. Se analizaron los tiempos de espera y la productividad para siete procedimientos quirúrgicos y cuatro procedimientos diagnósticos seleccionados sobre la base de su frecuencia relativa y comparabilidad con otros sistemas de salud nacionales. Resultados. El tiempo de espera promedio para los siete procedimientos quirúrgicos en las tres instituciones fue de 14 semanas. Los hospitales del IMSS y el ISSSTE mostraron un mejor desempeño (12 y 13 semanas) frente a los hospitales de la SS (15 semanas). El tiempo de espera promedio para los cuatro procedimientos diagnósticos fue de 11 semanas. Los hospitales del IMSS mostraron un tiempo de espera promedio mejor (10 semanas) que los hospitales del ISSSTE (12 semanas) y la SS (11 semanas). Conclusión. Se identificaron variaciones importantes no sólo entre instituciones sino también al interior de cada una de ellas. Estas variaciones deben atenderse para así mejorar la satisfacción de los usuarios de los servicios.

Adenosina trifosfato bioluminescência para avaliação da limpeza de superfícies: uma revisão integrativa / Adenosine triphosphate bioluminescence to evaluate the effectiveness of surface cleaning: an integrative review / Bioluminiscencia adenosina trifosfato para evaluar la eficacia de la limpieza de superficies: una revisión integrativa

Objetivo: Identificar na literatura indicações e controvérsias do ATP bioluminescência para avaliação da efetividade da limpeza de superfícies em estabelecimentos de saúde. Método: Revisão integrativa da literatura, entre 2000 e 2012, nas bases de dados MEDLINE, LILACS, Science Direct, SCOPUS e Isi Web of Knowledge. Resultados: Selecionou-se para esta revisão 15 artigos. O ATP bioluminescência foi apontado como importante recurso educacional e método complementar à inspeção visual e às análises microbiológicas na avaliação da efetividade da limpeza. A impossibilidade de indicar a contaminação da superfície por micro-organismos viáveis, a interferência por substâncias químicas e a dificuldade de interpretação dos resultados constituem as principais controvérsias para o uso deste nos serviços de saúde. Conclusão: Apesar de constituir importante recurso na avaliação da limpeza de superfícies, mais estudos são necessários para incorporação efetiva do método nos serviços de saúde. .

Objective: To identify indications and controversies in the literature of the use of ATP bioluminescence to evaluate the effectiveness of surface cleaning in healthcare facilities. Method: Integrative literature review between 2000 and 2012 in the following databases: MEDLINE, LILACS, Science Direct, SCOPUS and Isi Web of Knowledge. Results: were selected for this review 15 articles. The ATP bioluminescence was considered an important educational resource and complementary method to visual inspection and microbiological evaluation of the effectiveness of cleaning. The impossibility to indicate surface contamination by microorganisms, interference by chemicals and the difficulty of interpreting the results constitute the main controversies in the use of ATP in health services. Conclusion: Although this is an important resource in the evaluation of surface cleaning, more studies are necessary for effective incorporation of the method in health services. .

Objetivo: Identificar en la literatura las indicaciones y controversias sobre el uso de la bioluminiscencia ATP para evaluar la eficacia de la limpieza de superficies en los servicios de salud. Método: Revisión integrativa de la literatura, entre 2000 y 2012, en las siguientes bases de datos: MEDLINE, LILACS, Science Direct, SCOPUS e ISI Web of Knowledge. Resultados: Se seleccionaron para esta revisión 15 artículos. La bioluminiscencia del ATP se considera un importante recurso educativo y método complementario a la inspección visual y la análisis microbiológica de la evaluación de la efectividad de la limpieza. La imposibilidad de indicar contaminación de la superficie por los microorganismos, la interferencia por los productos químicos y la dificultad de interpretar los resultados constituyen las principales controversias en la utilización de ATP en los servicios de salud. Conclusión: Aunque esto es un elemento importante en la evaluación de limpieza de superficies, se necesitan más estudios para incorporación eficaz del método en los servicios de salud. .

Influence of Apical Enlargement in Cleaning of Curved Canals Using Negative Pressure System

This study aimed to evaluate, by scanning electron microscopy (SEM), the cleaning of canal walls with moderate curvature subjected to biomechanical preparation with different final diameters using apical negative pressure irrigation. Thirty-two mesiobuccal roots of molars were divided into 4 groups (n=8) according to the instrument's final diameter: GI: 30.02, GII: 35.02, GIII: 40.02 and GIV: 45.02. Irrigating procedure was performed at each change of instrument with 1% NaOCl using the Endovac system. Final irrigation was conducted with 17% EDTA for 5 min. The SEM photomicrographs were evaluated under 35× and 1000× magnification, by three calibrated examiners, in a double-blind design. Data were submitted to Kruskal-Wallis and Dunn's post hoc tests (α=0.05). Canals instrumented with 30.02 and 35.02 final diameters showed more debris, statistically different from the other groups (p<0.05). Comparing each root canal third, for the cervical and apical portions no statistically significant difference (p>0.05) was found among the four groups. Regarding the presence of smear layer, canals with 30.02 final diameter showed the highest scores, statistically different from the 45.02 group (p<0.05) and similar to the 35.02 and the 40.02 groups (p>0.05). Although none of the studied diameters completely removed debris and smear layer, it may be concluded that instrumentation with higher final diameters was more effective in cleaning the root canals with moderate curvature.

Este estudo buscou avaliar, por meio de microscopia eletrônica de varredura (MEV), a limpeza das paredes de canais com curvatura moderada, submetidos ao preparo biomecânico com diferentes diâmetros finais utilizando-se irrigação por pressão apical negativa. Trinta e duas raízes mésio-vestibulares de molares foram divididas em 4 grupos (n=8) de acordo com o diâmetro final dos instrumentos: GI: 30.02, GII: 35.02, GIII: 40.02 e GIV: 45.02. O procedimento de irrigação foi realizado a cada troca de instrumento com NAOCl 1% utilizando o sistema EndoVac. A irrigação final foi conduzida com EDTA 17% por 5 min. As microfotografias de MEV foram avaliadas sob aumentos de 35× e 1000×, por três examinadores calibrados, em estudo duplo-cego. Os dados foram submetidos ao teste de Kruskal-Wallis e pós-teste de Dunn (=0,05). Os canais instrumentados com diâmetros finais de 30.02 e 35.02 demonstraram mais debris, estatisticamente diferente dos demais grupos (p<0,05). Comparando-se cada terço do canal radicular, para as porções cervical e apical não foi encontrada diferença estatisticamente significante (p>0,05) entre os quatro grupos. Com relação à presença de smear layer, canais com diâmetro final de 30.02 demonstraram os maiores scores, estatisticamente diferente do grupo 45.02 (p<0,05) e similar aos grupos 35.02 e 40.02 (p>0,05). Apesar de nenhum dos diâmetros estudados ter removido completamente os debris e a smear layer, pode ser concluído que a instrumentação com diâmetros finais maiores foi mais efetiva na limpeza dos canais radiculares com curvatura moderada.

Study on adherecce to capecitabine among patiens with colorectal cancer and meetastatic breast cancer / Estudo de aderência a capecitabina em pacientes com câncer colorretal e câncer de mama metastático

Context Capecitabine, an oral drug, is as effective as traditional chemotherapy drugs. Objectives To investigate the adhesion to treatment with oral capecitabine in breast and colorectal cancer, and to determine any correlation with changes in patient’s quality of life. Methods Patients with colorectal cancer or breast cancer using capecitabine were included. The patients were asked to bring any medication left at the time of scheduled visits. The QLQ-C30 questionnaire was applied at the first visit and 8-12 weeks after treatment. Results Thirty patients were evaluated. Adherence was 88.3% for metastatic colon cancer, 90.4% for non-metastatic colon cancer, 94.3% for rectal cancer and 96.2% for metastatic breast cancer. No strong correlation between adherence and European Organisation for Research and Treatment of Cancer QLQ-C30 functional or symptom scale rates had been found. There was no statistically significant correlation between compliance and the functional and symptom scales of the questionnaire before and after chemotherapy, with the exception of dyspnea. Conclusions Although no absolute adherence to oral capecitabine treatment had been observed, the level of adherence was good. Health professionals therefore need a greater focus in the monitoring the involvement of patients with oral treatment regimens. Patients with lesser degrees of dyspnea had greater compliance. .

Contexto A capecitabina, uma droga oral, é tão eficaz quanto as drogas quimioterápicas tradicionais. Objetivos Investigar a adesão ao tratamento oral com capecitabina para câncer de mama e colorretal e determinar qualquer correlação com as mudanças na qualidade de vida do paciente. Métodos Pacientes com câncer colorretal ou de mama em uso de capecitabina foram incluídos. A cada consulta os pacientes trouxeram a medicação restante. O questionário de qualidade de vida QLQ- C30 foi aplicado na primeira visita e 8-12 semanas após o tratamento. Resultados Trinta pacientes foram avaliados. A adesão foi de 88,3% para o câncer de cólon metastático, 90,4% para o de cólon não-metastático, 94,3% para o de reto e 96,2% para o de mama metastático. Com exceção da dispnéia, não houve forte correlação entre adesão e as taxas European Organisation for Research and Treatment of Cancer QLQ-C30 em relação a escala funcional ou de sintomas no início ou após quimioterapia. Conclusões O nível de adesão foi bom, embora não houvesse adesão absoluta ao tratamento com capecitabina oral. Os profissionais de saúde, portanto, precisam dar maior atenção a pacientes em regimes de tratamento oral. Os pacientes com menor grau de dispneia tiveram maior adesão. Neoplasias colorretais, terapia .

Farmacogenómica del tratamiento de primera línea en el cáncer gástrico: avances en la identificación de los biomarcadores genómicos de respuesta clínica / Pharmacogenomics of the first-line treatment for gastric cancer: advances in the identification of genomic biomarkers for clinical response to chemotherapy

Debido a la inespecificidad de los síntomas, el cáncer gástrico (CG) es diagnosticado frecuentemente en etapas avanzadas, lo que da cuenta de los altos índices de mortalidad debido a esta neoplasia a nivel mundial. El esquema de tratamiento adyuvante o neoadyuvante en los países occidentales incluye el uso de fluoropirimidinas citotóxicas y compuestos de platino formadores de aductos en el ADN. La respuesta clínica al tratamiento con estos fármacos depende principalmente de la sensibilidad del tumor, la cual a su vez está condicionada por el nivel de expresión de los blancos terapéuticos y de las enzimas de reparación del ADN. Sumado a esto, algunos polimorfismos de línea germinal en genes asociados al metabolismo y a la respuesta a estos fármacos, han mostrado asociación con respuestas pobres y con el desarrollo de eventos adversos, incluso con resultados fatales. La identificación de biomarcadores genómicos, en la forma de polimorfismos genéticos o la expresión diferencial de genes específicos asociados a la respuesta quimioterapeútica ha sido motivo de intensa investigación como base para la aplicación de la farmacogenómica en el establecimiento de una terapia farmacológica racional y personalizada del CG. Sin embargo, ante la eventual aplicación de la farmacogenómica en el ámbito clínico, es necesario establecer el valor pronóstico real de dichos biomarcadores mediante los estudios de asociación genotipo-fenotipo, así como su prevalencia en el contexto de cada población de pacientes. Estos aspectos son indispensables al evaluar la relación costo-efectividad de la introducción de los productos de la medicina genómica predictiva en el tratamiento del CG.

Gastric cancer (GC) is often diagnosed at later stages due to the lack of specificity of symptoms associated with the neoplasm, causing high mortality rates worldwide. The first line of adjuvant and neoadjuvant treatment includes cytotoxic fluoropyrimidines and platin-containing compounds which cause the formation of DNA adducts. The clinical outcome with these antineoplastic agents depends mainly on tumor sensitivity, which is conditioned by the expression level of the drug targets and the DNA-repair system enzymes. In addition, some germ line polymorphisms, in genes linked to drug metabolism and response to chemotherapy, have been associated with poor responses and the development of adverse effects, even with fatal outcomes in GC patients. The identification of genomic biomarkers, such as individual gene polymorphisms or differential expression patterns of specific genes, in a patient-by-patient context with potential clinical application is the main focus of current pharmacogenomic research, which aims at developing a rational and personalized therapy (i.e., a therapy that ensures maximum efficacy with no predictable side effects). However, because of the future application of genomic technologies in the clinical setting, it is necessary to establish the prognostic value of these genomic biomarkers with genotype-phenotype association studies and to evaluate their prevalence in the population under treatment. These issues are important for their cost-effectiveness evaluation, which determines the feasibility of using these medical genomic research products for GC treatment in the clinical setting.

Use of microRNAs in directing therapy and evaluating treatment response in colorectal cancer / Utilização dos microRNAs no direcionamento da terapia e na avaliação da resposta ao tratamento do câncer colorretal

Colorectal cancer is the third most common cancer worldwide. Survival and prognosis depend on tumor stage upon diagnosis, and in more than 50% of cases, the tumor has already invaded adjacent tissues or metastasis has occurred. Aiming to improve diagnosis, clinical prognosis and treatment of patients with colorectal cancer, several studies have investigated microRNAs as molecular markers of the disease due to their potential regulatory functions on tumor suppressor genes and oncogenes. This review aimed to summarize the main topics related to the use of microRNAs in diagnosis, clinical prognosis and evaluating treatment response in colorectal cancer.

O câncer colorretal é o terceiro tipo de câncer mais comum em todo o mundo. A sobrevivência e o prognóstico dependem do estágio do tumor no diagnóstico, momento em que, em mais de 50% dos casos, o tumor já invadiu tecidos adjacentes ou ocorreu metástase. Objetivando-se melhorar o diagnóstico, o prognóstico clínico e o tratamento de pacientes com câncer colorretal, vários estudos investigaram microRNAs como marcadores moleculares da doença, devido à sua função reguladora potencial sobre genes supressores de tumor e oncogenes. Esta revisão procura resumir os principais tópicos relacionados ao uso de microRNAs no diagnóstico, na determinação do prognóstico clínico e na avaliação de resposta ao tratamento do câncer colorretal.

A spheroid-based 3-D culture model for pancreatic cancer drug testing, using the acid phosphatase assay

Current therapy for pancreatic cancer is multimodal, involving surgery and chemotherapy. However, development of pancreatic cancer therapies requires a thorough evaluation of drug efficacy in vitro before animal testing and subsequent clinical trials. Compared to two-dimensional culture of cell monolayer, three-dimensional (3-D) models more closely mimic native tissues, since the tumor microenvironment established in 3-D models often plays a significant role in cancer progression and cellular responses to the drugs. Accumulating evidence has highlighted the benefits of 3-D in vitro models of various cancers. In the present study, we have developed a spheroid-based, 3-D culture of pancreatic cancer cell lines MIAPaCa-2 and PANC-1 for pancreatic drug testing, using the acid phosphatase assay. Drug efficacy testing showed that spheroids had much higher drug resistance than monolayers. This model, which is characteristically reproducible and easy and offers rapid handling, is the preferred choice for filling the gap between monolayer cell cultures and in vivo models in the process of drug development and testing for pancreatic cancer.

Síndrome hemolítico-urémico asociado al uso de gemcitabina: Caso clínico / Hemolytic-uremic syndrome associated with gemcitabine use: Report of one case

Gemcitabine is a widely used drug in the treatment of advanced pancreatic cancer and other malignancies. It is generally well tolerated and exceptionally its use has been associated with hemolytic-uremic syndrome, causing acute kidney injury, hipertension, chronic renal failure requiring dialysis, and death. We report a 60-year-old man with pancreatic carcinoma and regional lymph node invasion, whom after four months of therapy with gemcitabine and after dose number 11, suddenly developed an acute nephritic syndrome with moderate renal impairment, associated with severe anemia (hemoglobin 6.0 g/dL) and thrombocytopenia (20,000 mm³). Renal biopsy showed the classic findings of thrombotic micro angiopathy Gemcitabine was discontinued and renal function and hematological parameters gradually improved.

The epigenetic modifiers 5-aza-2'-deoxycytidine and trichostatin A influence adipocyte differentiation in human mesenchymal stem cells

Epigenetic mechanisms such as DNA methylation and histone modification are important in stem cell differentiation. Methylation is principally associated with transcriptional repression, and histone acetylation is correlated with an active chromatin state. We determined the effects of these epigenetic mechanisms on adipocyte differentiation in mesenchymal stem cells (MSCs) derived from bone marrow (BM-MSCs) and adipose tissue (ADSCs) using the chromatin-modifying agents trichostatin A (TSA), a histone deacetylase inhibitor, and 5-aza-2′-deoxycytidine (5azadC), a demethylating agent. Subconfluent MSC cultures were treated with 5, 50, or 500 nM TSA or with 1, 10, or 100 µM 5azadC for 2 days before the initiation of adipogenesis. The differentiation was quantified and expression of the adipocyte genes PPARG and FABP4 and of the anti-adipocyte gene GATA2 was evaluated. TSA decreased adipogenesis, except in BM-MSCs treated with 5 nM TSA. Only treatment with 500 nM TSA decreased cell proliferation. 5azadC treatment decreased proliferation and adipocyte differentiation in all conditions evaluated, resulting in the downregulation of PPARG and FABP4 and the upregulation of GATA2. The response to treatment was stronger in ADSCs than in BM-MSCs, suggesting that epigenetic memories may differ between cells of different origins. As epigenetic signatures affect differentiation, it should be possible to direct the use of MSCs in cell therapies to improve process efficiency by considering the various sources available.

Linfoma de Hodgkin con compromiso hepático tratado con esquema gemcitabina, dexametasona y cisplatino como puente para terapia estándar: Caso clínico / Hodgkin lymphoma with hepatic involvement treated with dexametasone, gemcitabine and cisplatin as a bridge to standard therapy: Report of one case

Background: The initial presentation of Hodgkin lymphoma with liver involvement is rare. In these patients, the standard first-line therapy with ABVD (Adriamycin, Bleomycine, Vinblastine, Dacarbazine) imply an additional risk for liver toxicity. We report a 64-year-old woman who presented with jaundice, choluria, malaise and weight loss. In the initial evaluation she had jaundice and palpable groin lymph nodes. An obstructive biliary disease was ruled out with magnetic resonance imaging studies. A lymph node biopsy showed a Hodgkins lymphoma, Mixed-cellularity subtype. Considering the liver dysfunction, an alternative scheme of chemotherapy with dexamethasone, gemcitabine and cisplatin (GDP) was administered. After 4 cycles, a significant improvement in liver hepatic function tests was reached and a conventional chemotherapy (ABVD) was begun. While the literature provides some low toxicity protocols for patients with liver involvement, favorable results of our clinical case report allows us to postulate GDP as an alternative for salvage therapy in these patients.

Síndrome mão-pé induzida por quimioterapia: relato de um caso / Hand-foot syndrome induced by chemotherapy: a case study / Síndrome mano-pie inducida por quimioterapia: relato de un caso

Objetivou-se relatar um caso de uma paciente que apresentou síndrome mão-pé de grau 3, decorrente do uso do quimioterápico Capecitabina e para a qual foi utilizada massagem local com creme hidratante aquoso à base de aloe vera. A capacidade funcional da paciente foi avaliada utilizando-se a Escala de Performance ECOG e as lesões fotografadas durante as consultas de enfermagem que ocorreram em intervalos de dez dias, totalizando quarenta dias de acompanhamento. Observou-se melhora significativa da integridade tissular, com regressão total dos sintomas, importante ganho em qualidade de vida, e retorno imediato ao tratamento quimioterápico. Acredita-se que o aloe vera pode ser um importante coadjuvante na assistência de enfermagem a pacientes submetidos à quimioterapia antineoplásica.

The study was aimed at reporting a case of a patient who developed Hand-Foot Syndrome (HFS) grade 3 due the use of capecitabine and for which massage was used with aqueous-based moisturizer, aloe vera. The patient's functional capacity was assessed using the ECOG Performance Scale and the lesions were photographed during nursing appointment that occurred at intervals of ten days, totaling forty days of monitoring. There was significant improvement in tissue integrity, with total regression of symptoms, an important gain in quality of life, and immediate return to chemotherapy. It is believed that aloe vera can be an important component in nursing care in patients undergoing cancer chemotherapy.

El estudio tiene como objetivo presentar un caso de una paciente que desarrolló la Síndrome Pie-Mano de grado 3 debido al uso de capecitabina y en que se utilizó el masaje con crema hidratante aloe vera, en base acuosa. La capacidad funcional de la paciente se evaluó mediante la Escala de Desempeño ECOG y las lesiones fueran fotografiadas durante las consultas de enfermería que ocurrirán a intervalos de diece días, con un total de cuarenta días de seguimiento. Hubo una mejora significativa en la integridad de los tejidos, con la regresión total de los síntomas, un aumento importante en la calidad de vida, y el retorno inmediato a la quimioterapia. Se cree que el aloe vera puede ser un componente importante en los cuidados de enfermería en pacientes sometidos a quimioterapia contra el cáncer.

Combination of gemcitabine and carboplatin in urothelial cancer patients unfit for cisplatin due to impaired renal or cardiac function

PURPOSE: Combination of gemcitabine and carboplatin is the accepted treatment for metastatic urothelial cancer patients unfit for cisplatin-based chemotherapy. MATERIALS AND METHODS: Gemcitabine 1000 mg/m² (days 1, 8) and carboplatin AUC-4.5 (day 1) were given every 21 days to 23 patients with creatinine clearance < 60 mL/min, cardiac ejection fraction < 45% or active ischemia. Patient characteristics included: median age 73 (56-86) years; primary site: bladder 17 (73%), upper tract 6 (27%) patients; Bajorin's prognostic groups: good 6 (26%), intermediate 11 (48%) and poor 6 (26%) patients. Data was retrospectively documented. Patients were followed until they expired. RESULTS: We obtained objective responses in 8 (34.7%) patients, (95% CI, 16.3-57.2%), including one patient with complete response. The median progression-free survival was 4 (0.2-16.5+) months and the overall survival 8.6 (0.2-45.3+) months. At time of analysis, 4 patients (17%) remained disease free; 3 of them underwent resection of residual disease. Toxicity included: infection in 9 (39%) patients; among them, one died from pneumonia; bleeding > grade 2 in 3 (13%) patients and fatigue grade 3 in 2 (9%) patients. Hematologic toxicity included grade 4 thrombocytopenia in 2 (9%) patients and grade 4 neutropenia in 3 (13%) patients. Five (22%) patients discontinued therapy due to toxicity. CONCLUSIONS: Combination of gemcitabine and carboplatin demonstrated clinical activity in patients with advanced urothelial cancer unfit for cisplatin. It was associated with considerable toxicity. Resection of residual disease is feasible in this population.