Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing?

Imatinib is the standard of care for patients with advanced metastatic gastrointestinal stromal tumors (GIST), and is also approved for adjuvant treatment in patients at substantial risk of relapse. Studies have shown that maximizing benefit from imatinib depends on long-term administration at recommended doses. Pharmacokinetic (PK) and pharmacodynamic factors, adherence, and drug-drug interactions can affect exposure to imatinib and impact clinical outcomes. This article reviews the relevance of these factors to imatinib's clinical activity and response in the context of what has been demonstrated in chronic myelogenous leukemia (CML), and in light of new data correlating imatinib exposure to response in patients with GIST. Because of the wide inter-patient variability in drug exposure with imatinib in both CML and GIST, blood level testing (BLT) may play a role in investigating instances of suboptimal response, unusually severe toxicities, drug-drug interactions, and suspected non-adherence. Published clinical data in CML and in GIST were considered, including data from a PK substudy of the B2222 trial correlating imatinib blood levels with clinical responses in patients with GIST. Imatinib trough plasma levels <1100ng/mL were associated with lower rates of objective response and faster development of progressive disease in patients with GIST. These findings have been supported by other analyses correlating free imatinib (unbound) levels with response. These results suggest a future application for imatinib BLT in predicting and optimizing therapeutic response. Nevertheless, early estimates of threshold imatinib blood levels must be confirmed prospectively in future studies and elaborated for different patient subgroups.

Anti-VEGFA therapy reduces tumor growth and extends survival in a murine model of ovarian granulosa cell tumor

Les tumeurs des cellules de la granulosa (GCTs) sont des tumeurs avec un potentiel malin ayant tendance à récidiver, provoquant ainsi la mort dans 80% des cas de stade avancé consécutif à une rechute. Bien que les GCTs représentent 5% des tumeurs ovariennes, peu d’études ont évalué les protocoles de traitement adjuvant pour la maladie avancée ou récurrente. Notre but était d’évaluer l’efficacité de la voie de signalisation du facteur de croissance de l’endothélium vasculaire A (VEGFA) comme cible pour le traitement de la GCT utilisant le modèle murin transgénique Ptentm1Hwu/tm1Hwu; Ctnnb1tm1Mmt/+; Amhr2tm3(cre)Bhr/+ (PCA) qui reproduit le stade avancé de la maladie humaine. Un anticorps anti-VEGFA a été administré une fois par semaine par voie intrapéritonéale (IP) à partir de 3 semaines d’âge. La thérapie anti-VEGFA a permis une réduction de la taille des tumeurs à 6 semaines d’âge (p<0.05) et une prolongation de la survie des animaux traités, lorsque comparé aux animaux contrôles. L’analyse des GCTs a montré une réduction significative de la prolifération cellulaire (p<0.05) et de la densité microvasculaire (p<0.01) mais aucune différence significative n’a été détectée dans l’apoptose cellulaire. p44/p42 MAPK, un effecteur de la signalisation pour le récepteur 2 de VEGFA (VEGFR2) associé à la prolifération cellulaire, était moins activé dans les tumeurs traitées (p<0.05). Par contre, l’activation d’AKT, un effecteur impliqué dans la survie cellulaire, était similaire d’un groupe à l’autre. Ces résultats suggèrent que l’anticorps anti-VEGFA réduit la prolifération cellulaire et la densité microvasculaire chez les souris PCA par inhibition de la voie de signalisation VEGFR2-MAPK, inhibant ainsi la croissance tumorale. En conclusion, l’efficacité de la thérapie anti- VEGFA mérite d’être évaluée en essais contrôlés randomisés pour le traitement des GCTs chez l’homme.

Terapia electroconvulsiva en esquizofrenia resistente a tratamiento farmacológico

El uso de la terapia electroconvulsiva en el tratamiento de la esquizofrenia resistente a manejo farmacológico suscita en la actualidad diferentes posiciones respecto a su utilidad y eficacia en el control del espectro de síntomas presentados por este tipo de pacientes. Objetivo: Determinar la efectividad de la terapia electroconvulsiva en esquizofrenia resistente a tratamiento farmacológico. Materiales y métodos: Se realizó una revisión sistemática de la literatura. Se incluyeron dos estudios aleatorizados controlados y siete estudios abiertos cuasi experimentales. Se excluyeron 12 estudios y otros cinco estudios se clasificaron en curso, es decir, que a la fecha no se han terminado ni publicado. Resultados: La evidencia disponible, respalda el uso de la terapia electroconvulsiva como terapia coadyuvante al tratamiento farmacológico en pacientes con esquizofrenia refractaria. Un grupo de cuatro estudios cuasi experimentales mostró reducción clínicamente significativa de la escala BPRS al igual que los dos estudios aleatorizados controlados. El grupo restante de tres estudios cuasi experimentales, mostró reducción clínicamente significativa de la escala PANSS. Estos resultados, se dan en el marco de la existencia de pocos ensayos clínicos aleatorizados disponibles. Conclusiones: La TEC combinada con medicamento antipsicótico provee la mejor opción terapéutica en el tratamiento agudo y a largo plazo de la esquizofrenia refractaria. Es necesaria la realización de estudios clínicos que aporten mayor nivel de evidencia.

Uso de metilprednisolona como tratamento adjuvante do choque hipovolémico, distributivo e séptico

Hoje em dia, o uso abusivo de corticosteroide nos vários tipos de choque(hipovolémico,distributivo e séptico) tem levado a debates polémicos. Ao comparar, os resultados dos inúmeros autores que abordaram este tema, não é possível tirar uma conclusão unânime. A opinião de cada um diverge, havendo autores que apoiam e outros que refutam a sua utilização no choque. O objetivo deste estudo consiste em verificar se o uso metilprednisolona vai surtir algum benefício na reversão e sobrevivência do choque, nos animais, em que a terapêutica inicial de abordagem ao choque não tenha surtido efeito. O presente estudo foi realizado no Hospital Veterinário da Arrábida (HVA), em Azeitão, ao longo de um período de 7 meses, decorrido entre 1 de Setembro de 2011 até 31 Março de 2012. Durante esse tempo, procedeu-se ao acompanhamento de 57 animais em choque hipovolémico, distributivo ou séptico. Nas primeiras horas após ser instituído a fluidoterapia de choque e vasopressores, existiram animais em estudo que não conseguiu estabilizar a pressão arterial média (PAM) dentro dos valores normais de referência. Nestes casos foi administrado um tratamento adjuvante com metilprednisolona. Através da análise descritiva da população em estudo verificou-se que a taxa de mortalidade foi menor no grupo de canídeos e felídeos em que não se efetuou o tratamento adjuvante com metilprednisolona.

Rastreio Serológico de Toxoplasmose em Gatos dos Concelhos de Oeiras e Cascais

A toxoplasmose é uma das parasitoses mais comuns em gatos sendo que a sua seroprevalência mundial varia entre 5,5% e 97,4%. Em Portugal, existem poucos estudos sobre a prevalência da toxoplasmose e, por isso, este estudo tem como objetivo principal contribuir para o conhecimento da seroprevalência de base clínica no nosso país. Para a sua realização, foram colhidas amostras de soro de 63 gatos e recolhidos dados epidemiológicos sobre a idade, a raça, o género, o tipo de alimentação, o acesso ao exterior e o tipo de habitat dos progenitores. As amostras de soro foram analisadas através da técnica de imunofluorescência indireta, tendo sido encontrados 25 gatos seropositivos, correspondendo a uma seroprevalência de base clínica de 41%. O único fator de risco identificado foi o acesso ao exterior. A idade do animal não foi estatisticamente significativa como fator de risco, mas observou-se um aumento da prevalência em animais até aos 6 anos de idade. Os gatos de progenitores com acesso ao exterior, animais de género feminino e com alimentação de risco apresentaram maior número de seropositivos, no entanto, estes resultados não foram estatisticamente significativos.

Investigation of the effects of the novel anticonvulsant compound carisbamate(RWJ-333369) on rat piriform cortical neurones in vitro

Background and purpose: Carisbamate is being developed for adjuvant treatment of partial onset epilepsy. Carisbamate produces anticonvulsant effects in primary generalized, complex partial and absence-type seizure models, and exhibits neuroprotective and antiepileptogenic properties in rodent epilepsy models. Phase IIb clinical trials of carisbamate demonstrated efficacy against partial onset seizures; however, its mechanisms of action remain unknown. Here, we report the effects of carisbamate on membrane properties, evoked and spontaneous synaptic transmission and induced epileptiform discharges in layer II-III neurones in piriform cortical brain slices. Experimental approach: Effects of carisbamate were investigated in rat piriform cortical neurones by using intracellular electrophysiological recordings. Key results: Carisbamate (50–400 mmol·L-1) reversibly decreased amplitude, duration and rise-time of evoked action potentials and inhibited repetitive firing, consistent with use-dependent Na+ channel block; 150–400 mmol·L-1 carisbamate reduced neuronal input resistance, without altering membrane potential. After microelectrode intracellular Cl- loading, carisbamate depolarized cells, an effect reversed by picrotoxin. Carisbamate (100–400 mmol·L-1) also selectively depressed lateral olfactory tract-afferent evoked excitatory synaptic transmission (opposed by picrotoxin), consistent with activation of a presynaptic Cl conductance. Lidocaine (40–320 mmol·L-1) mimicked carisbamate, implying similar modes of action. Carisbamate (300–600 mmol·L-1) had no effect on spontaneous GABAA miniature inhibitory postsynaptic currents and at lower concentrations (50–200 mmol·L-1) inhibited Mg2+-free or 4-aminopyridine-induced seizure-like discharges. Conclusions and implications: Carisbamate blocked evoked action potentials use-dependently, consistent with a primary action on Na+ channels and increased Cl- conductances presynaptically and, under certain conditions, postsynaptically to selectively depress excitatory neurotransmission in piriform cortical layer Ia-afferent terminals.

Current level of consensus on probiotic science: report of an expert meeting, London, 23 November 2009

The present paper summarizes  the consensus views of a group of 9 European clinicians and scientists on the current state of scientific knowledge on probiotics, covering those areas where there is substantial evidence for beneficial effects and those  where the evidence base is poor or inconsistent. There was general agreement that probiotic effects were species and often strain specific. The experts agreed  that some probiotics were effective in reducing the incidence and duration of rotavirus diarrhoea in infants, antibiotic-associated diarrhoea in adults and, for certain probiotics, Clostridium difficile infections. Some probiotics are associated with symptomatic improvements in irritable bowel syndrome and alleviation of digestive discomfort. Probiotics can reduce the frequency and severity of necrotizing enterocolitis in premature infants and have been shown to regulate intestinal immunity.  Several other clinical effects of probiotics, including their role in inflammatory bowel disease, atopic dermatitis, respiratory or genito-urinary infections or H.pylori adjuvant treatment were thought promising but inconsistent.

Fisioterapia respiratória em crianças com pneumonia: revisão sistemática

Introduction: Pneumonia is an inflammatory lung disease and it is the greatest cause of deaths in children younger than five years of age worldwide. Chest physiotherapy is widely used in the treatment of pneumonia because it can help to eliminate inflammatory exudates and tracheobronchial secretions, remove airway obstructions, reduce airway resistance, enhance gas exchange and reduce the work of breathing. Thus, chest physiotherapy may contribute to patient recovery as an adjuvant treatment even though its indication remains controversial. Objectives: To assess the effectiveness of chest physiotherapy in relation to time until clinical resolution in children (from birth up to 18 years old) of either gender with any type of pneumonia. Methods: We searched CENTRAL 2013, Issue 4; MEDLINE (1946 to May week 4, 2013); EMBASE (1974 to May 2013); CINAHL (1981 to May 2013); LILACS (1982 to May 2013); Web of Science (1950 to May 2013); and PEDro (1950 to May 2013). We consulted the ClinicalTrials.gov and the WHO ICTRP registers to identify planned, ongoing and unpublished trials. We consulted the reference lists of relevant articles found by the electronic searches for additional studies. We included randomised controlled trials (RCTs) that compared chest physiotherapy of any type with no chest physiotherapy in children with pneumonia. Two review authors independently selected the studies to be included in the review, assessed trial quality and extracted data. Results: Three RCTs involving 255 inpatient children are included in the review. They addressed conventional chest physiotherapy, positive expiratory pressure and continuous positive airway pressure. The following outcomes were measured: duration of hospital stay, time to clinical resolution (observing the following parameters: fever, chest indrawing, nasal flaring, tachypnoea and peripheral oxygen saturation levels), change in adventitious sounds, change in chest X-ray and duration of cough in days. Two of the included studies found a significant improvement in respiratory rate and oxygen saturation whereas the other included study failed to show that standardised respiratory physiotherapy and positive expiratory pressure decrease the time to clinical resolution and the duration of hospital stay. No adverse effects related to the interventions were xvi described. Due to the different characteristics of the trials, such as the duration of treatment, levels of severity, types of pneumonia and the techniques used in children with pneumonia, as well as differences in their statistical presentation, we were not able to pool data. Two included studies had an overall low risk of bias whereas one included study had an overall unclear risk of bias. Conclusion: Our review does not provide conclusive evidence to justify the use of chest physiotherapy in children with pneumonia due to a lack of data. The number of included studies is small and they differed in their statistical presentation

Carcinoma espinocelular de conjuntiva com evolução para exenteração: relato de caso

Portador de carcinoma espinocelular da conjuntiva teve a lesão removida, com recorrência em outra localização. O paciente recebeu ciclos de 5-Fluoruracila como tratamento adjuvante à remoção cirúrgica, apresentando evolução desfavorável que chegou à exenteração orbitária. São feitos comentários quanto ao uso de antimitóticos no tratamento destas lesões.

Avaliação da expressão da proteína bcl-2 no carcinoma de mama: estudo em punção aspirativa por agulha fina; correlação com grau histológico em espécimes cirúrgicos correspondentes

INTRODUÇÃO: O gene bcl-2 codifica uma proteína envolvida no processo de controle da apoptose. Inicialmente descrito em linfomas e posteriormente em tecidos epiteliais, sua expressão é freqüentemente encontrada em carcinomas de mama, associada a fatores de prognóstico favorável. Como a punção aspirativa por agulha fina (PAAF) tem sido utilizada como um método confiável na investigação de carcinomas de mama, acessamos a expressão de bcl-2 em material assim obtido e correlacionamos sua positividade com o grau histológico, avaliado em material cirúrgico correspondente, das respectivas pacientes, seguindo a classificação de SBR (Scarff, Bloom e Richardson). OBJETIVOS: Avaliar a expressão de bcl-2 em PAAF e correlacionar com grau histológico. METODOLOGIA: A positividade do bcl-2 foi analisada, por imunocitoquímica, em 118 casos consecutivos de PAAF e correlacionada com grau histológico em material cirúrgico correspondente, segundo classificação de SBR. RESULTADOS: A positividade para bcl-2 foi encontrada em 77 de 118 casos de PAAF (65,25%) e foi inversamente proporcional ao grau histológico (84,37%, p = 0,0022). CONCLUSÃO: A expressão de bcl-2 em PAAF correlaciona-se com fator de bom prognóstico. O índice de positividade encontrado, assim como a correlação inversa com grau histológico, está de acordo com dados publicados previamente. O fácil e rápido manejo do material obtido por PAAF permite a aplicação de técnicas complementares, de maneira confiável, como demonstra este estudo. A positividade do bcl-2 correlacionada com baixo grau histológico, assim como com outros fatores de bom prognóstico, pode, no futuro, proporcionar informação preditiva e prognóstica para pacientes candidatas a tratamento quimioterápico neo-adjuvante.

Comparison between laser therapy and non-surgical therapy for periodontitis in rats treated with dexamethasone

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Glutathione transferase pi (GSTpi) expression in breast cancer: An immunohistochemical and molecular study

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Biostimulatory effects of low-level laser therapy on epithelial cells and gingival fibroblasts treated with zoledronic acid

Low-level laser therapy (LLLT) has been considered as an adjuvant treatment for bisphosphonate-related osteonecrosis, presenting positive clinical outcomes. However, there are no data regarding the effect of LLLT on oral tissue cells exposed to bisphosphonates. This study aimed to evaluate the effects of LLLT on epithelial cells and gingival fibroblasts exposed to a nitrogen-containing bisphosphonate - zoledronic acid (ZA). Cells were seeded in wells of 24-well plates, incubated for 48 h and then exposed to ZA at 5 μM for an additional 48 h. LLLT was performed with a diode laser prototype - LaserTABLE (InGaAsP - 780 nm ± 3 nm, 25 mW), at selected energy doses of 0.5, 1.5, 3, 5, and 7 J cm-2 in three irradiation sessions, every 24 h. Cell metabolism, total protein production, gene expression of vascular endothelial growth factor (VEGF) and collagen type I (Col-I), and cell morphology were evaluated 24 h after the last irradiation. Data were statistically analyzed by Kruskal-Wallis and Mann-Whitney tests at 5% significance. Selected LLLT parameters increased the functions of epithelial cells and gingival fibroblasts treated with ZA. Gene expression of VEGF and Col-I was also increased. Specific parameters of LLLT biostimulated fibroblasts and epithelial cells treated with ZA. Analysis of these in vitro data may explain the positive in vivo effects of LLLT applied to osteonecrosis lesions. © 2013 Astro Ltd.

Avaliação da resposta à quimiorradioterapia neoadjuvante em pacientes com adenocarcinomas retais

Pós-graduação em Bases Gerais da Cirurgia - FMB

Efeitos do laser e da terapia fotodinâmica no tratamento periodontal de ratas ovariectomizadas, com ou sem reposição hormonal: estudo histomorfométrico e imunoistoquímico

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)