Caracterización del riesgo de ingreso de encefalopatía espongiforme bovina a El Salvador mediante la importación de especies rumiantes y sus productos durante el periodo 2005-2015 / Characterization of the risk of ingress of bovine spongiform encephalopathy to El Salvador through the importation of ruminant species and their products during the period 2005-2015

El Salvador ha enfrentado dificultades para dar continuidad al proceso de categorización respecto a la Encefalopatía Espongiforme Bovina (EEB) ante la OIE, debido en parte a la deficiencia en la recopilación y ordenamiento de la información relativa a las importaciones de productos, subproductos y animales en pie por lo que la estimación y caracterización del riesgo de introducción de la enfermedad es mucho más difícil de realizar. En el presente trabajo se categorizo el riesgo de ingreso de EEB por las importaciones de origen rumiante, para que El Salvador eventualmente obtenga el reconocimiento sanitario por parte de la OIE para poder comercializar sus bovinos, productos y subproductos, hacia países con la misma condición sanitaria, se realizó una investigación descriptiva observacional, de carácter retrospectiva del periodo de 2005-2015, longitudinal mediante una revisión documental de archivos de las importaciones de productos de origen animal del Ministerio de Agricultura y Ganadería. Se describen un total de 15 países que importaron productos de riesgo en el periodo de 11 años identificando que el país recibe mayor cantidad de productos del área de América Central, teniendo esto poco valor significativo en cuanto al riesgo ya que estos países históricamente no han reportado casos de esta enfermedad. Realizando un cruce de variables de acuerdo al estatus del país de origen se determinó un Riesgo Medio de Introducción de la enfermedad a El Salvador, sin embargo esto representa solamente una parte de la información necesaria para obtener una categorización de País, al mismo tiempo esta investigación contribuye a mejorar los mecanismos de obtención, recopilación y clasificación de la información para tener mayor disponibilidad de datos que favorezcan la vigilancia epidemiológica y la toma de decisiones en la aplicación de medidas sanitarias encaminadas a disminuir el riesgo de ingreso de la EEB

Estrategia restrictiva transfusional en cirugía ortopédica / Restrictive transfusion strategy in orthopedics surgery

Para pacientes que sufren artrosis avanzada o en algunos casos de fractura de cadera, la solución quirúrgica que se propone es la cirugía ortopédica mayor. Alguno de estos pacientes requerirá transfusión de sangre o hemocomponentes, o ambos, antes o después de la intervención. El abordaje de la anemia en el paciente quirúrgico puede hacerse de manera liberal, sujeto a la indicación de cada cirujano, o en el contexto de un protocolo restrictivo de reposición. Con este último el beneficio en el ahorro de recursos se acompaña además de un menor número de complicaciones relacionadas con la administración de sangre alogénica. El objetivo específico de nuestro trabajo fue comparar la estrategia liberal con la terapia restrictiva transfusional. Ingresaron en el estudio 498 pacientes; de estos, 261 (52,4%) en el año 2014 sometidos a terapia liberal y 237 (47,6%) en el año 2015 a quienes se aplicó el protocolo de terapia restrictiva transfusional. Se transfundieron menos individuos y se indicaron 55% menos volúmenes de sangre con la estrategia restrictiva. Se presentaron diez casos de reacción transfusional, todas de tipo febril, ocho en 2014 y dos en 2015. Con respecto a la evolución funcional no se comprobó diferencia entre ambos grupos. En nuestra experiencia y de acuerdo a la literatura consultada, la terapia restrictiva permite alcanzar iguales resultados funcionales, con menor riesgo para el paciente y ahorraría recursos al sistema.

Major orthopedic surgery is the surgical solution proposed for patients who suffer from advanced arthrosis or for some cases of hip fracture. Some of these patients will require blood and/or blood components transfusion before or after surgery. The approach to anemia in surgical patients may involve a liberal or a restrictive transfusion strategy, according to what each surgeon indicates, or observing the context of a restrictive protocol for blood replacement. The latter results in resource savings and in a reduction in the number of complications due to the administration of allogenic blood. The study aims to compare the liberal transfusion strategy to the restrictive strategy. 498 patients were included in the study, 261 of which (52.4%) were treated within the liberal strategy in 2014, and 237 (47.6%) were treated according to a restrictive transfusion protocol in 2015. A smaller number of individuals received blood transfusions and 55% less blood volumes were needed when the restrictive strategy was applied. Ten cases of transfusion reaction arose, all of them involving fever, 8 in 2014 and 2 in 2015. As to the functional evolution, no differences were found between the two groups. According to our study, and according to the global literature consulted, the restrictive therapy strategy enables the same functional results with a lower risk for patients, and it saves resources for the system.

Para pacientes com artrose avançada ou em alguns casos de fratura de quadril, a solução cirúrgica que se propõe é a cirurgia ortopédica maior. Algum destes pacientes necessitará transfusão de sangue e/ou hemocomponentes antes ou depois da intervenção. A abordagem da anemia no paciente cirúrgico pode ser feita de maneira liberal, sujeito à indicação de cada cirurgião, ou seguindo um protocolo restritivo de reposição. Utilizando este último se observa um beneficio não só na economia de recursos como também por um menor número de complicações relacionadas com a administração de sangue alogênica. O objetivo específico deste trabalho foi comparar a estratégia liberal com a terapia restritiva transfusional. Foram incluídos no estudo 498 pacientes, sendo 261 (52,4%) em 2014 submetidos à terapia liberal, e 237 (47,6%) em 2015 quando se utilizou o protocolo de terapia restritiva transfusional. Umnúmero menor de pacientes necessitou transfusão sanguínea e foram indicados 55% menos volumes de sangre com a estratégia restritiva. Foram registrados 10 casos de reação transfusional, todas do tipo febril, oito em 2014 e 2 em 2015. Com respeito à evolução funcional, não foram observadas diferenças entre ambos os grupos. Na nossa experiência e de acordo com a literatura consultada, a terapia restritiva permite alcançar resultados funcionais iguais commenos riscos para o paciente e pouparia recursos ao sistema.

Estudio de una cohorte de pacientes con enfermedad tromboembólica venosa en seguimiento ambulatorio / Cohort study of pacients with venous thromboembolic disease assisted in ambulatory care / Estudo de umacoorte de pacientes comdoença tromboembólica venosa em acompanhamentoambulatorial

Resumen: La enfermedad tromboembólica venosa (ETEV) es una patología con morbilidad y mortalidad elevadas. Su manejo diagnóstico y terapéutico está en permanente revisión. La ausencia de estudios epidemiológicos en nuestro medio implica un desconocimiento de la forma de presentación, etiología y recurrencia de la misma. Se propone un estudio descriptivo sobre la población de pacientes con ETEV en seguimiento en la policlínica de Trombosis y Hemostasis del Hospital Pasteur de Montevideo, durante el período 2015-2016. Se registraron 35 pacientes con ETEV. La ETEV provocada se asoció predominantemente a factores de riesgo mayor y en los cuales falló la adecuada prescripción de tromboprofilaxis. En los pacientes con ETEV no provocada, las trombofilias diagnosticadas fueron el síndrome de anticuerpos anti fosfolípidos, déficit de Antitrombina y mutación del gen de la protrombina heterocigoto. Los pacientes con ETEV no provocada tuvieron un elevado porcentaje de recurrencias, la mitad de ellas asociadas a trombofilia y la otra mitad sin factor de riesgo predisponente (ETEV idopática).

Abstract: Venous thromboembolic disease (VTD) is a condition with high rates of morbidity and mortality. The etiologic diagnosis and therapeutics are in a continuous review process. In our country there are still no epidemiologic studies about the clinic presentation, etiology and recurrence of VTD. This is a cohort study of patients assisted in ambulatory care at the Thrombosis and Haemostasis Clinic of the Hospital Pasteur in Montevideo, for the 2015-2016 period. 35 patients were registered with VTD. Provoked VTD was associated with major risk factors in which optimal prescription of thromboprofilaxis failed. In patients with unprovoked VTD, testing for trombophiliashowed Antitrombin deficiency, hetrocigotic mutation of the Protrombin and antiphospholipid antibodies. Patients with unprovoked VTD showed a high percentage of recurrences, half of them with associated trombophilia and the otherhalf with no risk factor (idiopatic VTD).

Resumo: O tromboembolismo venoso (VTE) é umadoençacom elevada morbilidade e mortalidade. Diagnóstico e manejo terapêutico está em constante revisão. A ausência de estudos epidemiológicos em nosso ambiente implica uma falta de apresentação, etiologia e recorrência do mesmo. Umestudodescritivonapopulação de pacientes com TEV monitorizaçãoproposto no polyclinic de Thrombosis and Haemostasis Hospital Pasteur em Montevidéu, durante o período de 2015-2016. 35 doentescom tromboembolismo venoso foramregistados. TEV causado predominantemente associada a fatores de risco aumentado e que falhou a prescriçãoadequada de tromboprofilaxia. Em pacientes com TEV não provocado os trombofilia foram diagnosticados síndrome anti fosfolipídiosdeficiência de antitrombina e mutação do heterozigoto protrombina. TEV pacientes nãocausaramuma elevada taxa de recorrência, metade delas associadacom trombofilia e meiasempredispondo factor de risco (idiopática VTD).

Evaluación de la prescripción de trombo-profilaxis farmacológica y valoración del impacto que generan distintas estrategias para mejorar su indicación / Evaluation of the prescription of pharmacological thrombo-prophylaxis and assessment of the impact generated by different strategies to improve its indication

Resumen: Introducción: La enfermedad tromboembólica venosa (ETEV) constituye la principal causa de muerte prevenible en pacientes hospitalizados. Actualmente se encuentra validado el score de Padua para detectar los pacientes con patología médica con alto riesgo de ETEV. Objetivos: analizar la prescripción de tromboprofilaxis farmacológica en pacientes internados por patología médica y analizar el impacto que genera la realización de distintas estrategias para estimular la prescripción de la misma. Material y métodos: se realizó un corte transversal de todos los pacientes internados en cuidados moderados de medicina en diciembre 2014 aplicando el score de Padua. Tras varias intervenciones de educación, se realizó un segundo corte transversal un año después aplicando la misma herramienta. Resultados: 48/67 pacientes analizados en el primer corte tenían alto riesgo de trombosis, sólo 29 tenían indicación de tromboprofilaxis farmacológica. 32/52 pacientes analizados en el segundo corte tenían indicación, estando prescripta en 26 de los mismos (p: 0,0062) Discusión: la inclusión del score de Padua en las historias clínicas, la realización de instancias de revisión de guías, promoción de tromboprofilaxis y concientización de la ETEV en el personal médico aumentaron significativamente su prescripción.

Abstract: Introduction: Venous thromboembolic disease (VTE) is the leading cause of preventable death in hospitalized patients. The Padua score is currently validated to detect patients with medical pathology with a high risk of VTE. Objectives: to analyze the prescription of pharmacological thromboprophylaxis in patients hospitalized for medical pathology and to analyze the impact of different strategies to stimulate the prescription of thromboprophylaxis. Methods: A cross-sectional study was carried out of all patients admitted to moderate medical care in December 2014 applying the Padova score. After several educational interventions, a second cross-sectional study was carried out one year later using the same tool. Results: 48/67 patients analyzed in the first cut had a high risk of thrombosis, only 29 had an indication of pharmacological thromboprophylaxis. 32/52 patients analyzed in the second section had an indication, being prescribed in 26 of them (p: 0.0062) Discussion: inclusion of the Padua score in the medical records, implementation of guidelines review, promotion of Thromboprophylaxis and ETEV awareness in the medical staff significantly increased its prescription.

Síndrome de Brugada: a propósito de dos casos clínicos / Brugada Syndrome: report of two cases

Resumen: Desde su introducción como entidad clínica por los hermanos Brugada en la década del 90, el Síndrome de Brugada ha generado gran interés debido a su asociación con un alto riesgo de arritmias ventriculares y muerte súbita, en pacientes jóvenes con corazón estructuralmente normal. Se trata de una enfermedad genética, de transmisión autosómica dominante que determina alteraciones a nivel de canales iónicos en el tejido miocárdico. Tiene una presentación electrocardiográfica característica, siendo sus manifestaciones clínicas principales el síncope y la muerte súbita cardíaca.La presencia únicamente del patrón electrocardiográfico, en ausencia manifestaciones clínicas, no debe considerarse como un Síndrome de Brugada sino como un Patrón Brugada. El único tratamiento disponible y efectivo es la implantación de un cardiodesfibrilador automático definitivo. Es nuestro interés realizar una actualización del tema en función de 2 casos clínicos que asistimos.

Abstract Since its introduction as a clinical entity by the Brugada brothers in the 90s, the Brugada syndrome has generated great interest due to their association with an increased risk of ventricular arrhythmias and sudden death in young patients with structurally normal heart. This is a dominant genetic disease, autosomal that determines abnormalities in ion channels in myocardial tissue. ECG has a characteristic presentation, its main clinical manifestations syncope and sudden cardiac death. The presence of electrocardiographic pattern only in clinical manifestations absence should not be considered as a Brugada syndrome but as a Brugada pattern. The only available and effective treatment is the implantation of a permanent cardioverter defibrillator. Our interest is an upgrade of the issue based on two clinical cases that we attended.

Meningoencefalitis por Streptococcus suis.: Primeros dos casos en Uruguay. / Streptococcus suis meningoencephalitis: First two cases reported in Uruguay

La infección por Streptococcus suis (S. suis) es una zoonosis emergente, poco frecuente, secundaria a la exposición alimentaria o laboral a cerdos. La infección en los humanos se considera una enfermedad emergente con aparición de casos esporádicos, y más raramente brotes. Son un importante problema en la industria porcina a nivel mundial, ya que coloniza los tractos respiratorios, digestivo y genital del ganado porcino, siendo éstos portadores asintomáticos en 80% de los casos. En el humano S. suis causa una infección sistémica que puede afectar varios órganos. La meningitis es la manifestación más frecuente (68%); con menor frecuencia puede causar sepsis (25%), artritis (12,9%), endocarditis (12,4%) y endoftalmitis (4,6%). El tratamiento de elección para la meningitis a S. suis es la penicilina. En esta comunicación se presentan los primeros dos casos de meningoencefalitis causada por S. suis en Uruguay en 2008 y 2009. Un tercer caso se reportó en Paysandú en 2009.

Infection with Streptococcus suis (S. suis) is an uncommon emerging zoonosis, secondary to food or occupational exposure to pigs. Infection in humans is considered an emerging disease with onset of sporadic cases and outbreaks rarely. They are a major problem in the swine industry worldwide since colonizes the respiratory, digestive and genital tracts of pigs, they remain asymptomatic carriers in 80% of cases. In the human S. suis causes a systemic infection that can affect various organs. Meningitis is the most common presentation (68%), less often can cause sepsis (25%), arthritis (12.9%), endocarditis (12.4%) and endophthalmitis (4.6%). The treatment of choice for S suis meningitis is penicillin. In this communication the first two cases of meningoencephalitis caused by S. suis in Uruguay in 2008 and 2009. A third case was reported in Paysandú in 2009.

[Risk factors for community-acquired urinary tract infection caused by fluoroquinolone resistant E. coli]. / Factores asociados al desarrollo de infección urinaria de origen comunitario causada por Escherichia coli resistente a fluoroquinolonas.

Fluoroquinolones (FQ) are the most widely used drugs for the empirical treatment of urinary tract infection (UTI) in Uruguay. The rates of fluoroquinolone resistance are increasing. The objective was to determine the risk factors associated with the development of community-acquired UTI caused by fluoroquinolone-resistant Escherichia coli (ECRFQ). A descriptive, cross-sectional, prospective study of 525 patients with community-acquired UTI, who consulted at the Hospital Pasteur Emergency Department was carried. In 434 patients (82.7%) E. coli was the cause of UTI. Multivariate analysis identified as independent risk factors for the development of ECRFQ UTI, being older than 60 years (OR 2.52 95% CI 1.35 to 4.72), having obstructive uropathy (OR 2 09 95% CI 1.03 to 4.28) with recurrent UTI history (OR 2.98 95% CI 1.55 to 5.76) and / or use of FQ in the previous 3 months (OR 4.27 95% CI 1.88 to 9.71). Patients with these characteristics have a higher risk of ECRFQ UTI and should be treated with alternative drugs.

In vitro evaluation of the interaction potential of irosustat with drug-metabolizing enzymes.

Irosustat is a first-generation, irreversible, steroid sulfatase inhibitor currently in development for hormone-dependent cancer therapy. To predict clinical drug-drug interactions between irosustat and possible concomitantly administered medications, the inhibition/induction potential of irosustat with the main drug-metabolizing enzymes was investigated in vitro. The interaction of aromatase inhibitors in the in vitro metabolism of irosustat was also studied. Irosustat inhibited CYP1A2 activity in human liver microsomes through the formation of its desulfamoylated degradation product and metabolite 667-coumarin. CYP1A2 inhibition by 667-coumarin was competitive, with a K(i) of 0.77 µM, a concentration exceeding by only 5-fold the maximal steady-state concentration of 667-coumarin in human plasma with the recommended dose of irosustat. In addition, 667-coumarin metabolites enhanced the inhibition of CYP1A2 activity. Additional clinical interaction studies of irosustat with CYP1A2 substrate drugs are strongly recommended. 667-Coumarin also appeared to be a competitive inhibitor of CYP2C19 (K(i) = 5.8 µM) in human liver microsomes, and this inhibition increased with assessment in human hepatocytes. Inhibition of CYP2C19 enzyme activity was not caused by repression of CYP2C19 gene expression. Therefore, additional mechanistic experiments or follow-up studies with clinical evaluation are recommended. Irosustat neither inhibited CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5, or UDP-glucuronosyltransferase 1A1, 1A4, or 2B7 activities nor induced CYP1A2, CYP2C9, CYP2C19, or CYP3A4/5 at clinically relevant concentrations. Results from human liver microsomes indicated that no changes in irosustat pharmacokinetics in vivo are expected as a result of inhibition of irosustat metabolism in cases of concomitant medication administration or irosustat-aromatase inhibitor combination therapy with letrozole, anastrozole, or exemestane.

Quantitative proton MR spectroscopy as a biomarker of tumor necrosis in the rabbit VX2 liver tumor.

PURPOSE: To compare metabolic magnetic resonance (MR) imaging findings (ie, quantification of tumor choline concentration) with percentage of necrosis on pathologic examination in rabbits bearing VX2 liver tumors. MATERIALS AND METHODS: VX2 tumors were implanted in the livers of 16 rabbits. MR imaging was performed with a 1.5-T MR scanner and extremity coil, and a hydrogen-1 ((1)H) proton MR spectroscopy ((1)H MRS) imaging protocol was used. Rabbits were euthanized immediately after imaging, and the tumor was harvested and sliced at 4-mm intervals in the axial plane. Choline concentration was calculated and was compared with the percentage of tumor necrosis on pathologic examination. RESULTS: Mean tumor size at pathologic examination was 16 mm (range, 12-22 mm). Mean percentage of necrosis at pathologic examination was 22% (range, 4%-44%). Choline concentration showed a relatively high inverse correlation with percentage of necrosis on pathologic examination, with an r value of 0.78 (P < .002). CONCLUSIONS: Choline concentration showed a relatively high inverse correlation with tumor necrosis on pathologic examination. Therefore, (1)H MRS may be useful to assess tumor necrosis.

In vitro metabolism of irosustat, a novel steroid sulfatase inhibitor: interspecies comparison, metabolite identification, and metabolic enzyme identification.

Irosustat is a novel steroid sulfatase inhibitor for hormone-dependent cancer therapy. Its structure is a tricyclic coumarin-based sulfamate that undergoes desulfamoylation in aqueous solution, yielding the sulfamoyl-free derivative, 667-coumarin. The aim of the present work was to study the in vitro metabolism of irosustat, including its metabolic profile in liver microsomes and hepatocytes, the potential species differences, and the identification of the main metabolites and of the enzymes participating in its metabolism. Irosustat was extensively metabolized in vitro, showing similar metabolite profiles among rat, dog, monkey, and humans (both sexes). In liver microsomes, the dog was the species that metabolized irosustat most similarly to metabolism in humans. Marked differences were found between liver microsomes and hepatocytes, meaning that phase I and phase II enzymes contribute to irosustat metabolism. Various monohydroxylated metabolites of irosustat and of 667-coumarin were found in liver microsomes, which mostly involved hydroxylations at the C8, C10, and C12 positions in the cycloheptane ring moiety. 667-Coumarin was formed by degradation but also by non-NADPH-dependent enzymatic hydrolysis, probably catalyzed by microsomal steroid sulfatase. The main metabolites formed by hepatocytes were glucuronide and sulfate conjugates of 667-coumarin and of some of its monohydroxylated metabolites. The major cytochrome P450 enzymes involved in the transformation of irosustat were CYP2C8, CYP2C9, CYP3A4/5, and CYP2E1. Moreover, various phase II enzymes (UDP-glucuronosyltransferases and sulfotransferases) were capable of conjugating many of the metabolites of irosustat and 667-coumarin; however, the clinically relevant isoforms could not be elucidated.

Malacoplaquia diseminada: evoluciónexcepcional de una rara patología / Disseminated malakoplakia: exceptional development of an inusual pathology

La malacoplaquia es una enfermedad granulomatosa crónica que afecta principalmente el tracto genitourinario, si bien puede asentar en cualquier órgano de la economía, habitualmente autolimitada y benigna. Las formas extravesicales presentan un curso másagresivo. El diagnóstico es histopatológico, siendo patognomónicos los cuerpos de Michaelis-Guttmann. Se vincula a infecciones crónicas, enfermedades sistémicas, inmunodepresión y neoplasias. El tratamiento médico es inespecífico y en caso de masas voluminosas se plantea conducta quirúrgica. El pronóstico está íntimamente relacionado a la localización del proceso y a la presencia de enfermedades concomitantes.El caso de malacoplaquia reportado es excepcional por la presentación clínica (HDA reiteradas), por el origen topográfico, el compromiso ganglionar y la diseminación de la afección, así como por el curso evolutivo maligno de la misma.

Malakoplakia is a chronic disease which primarily affects the Genitourinary tract, although it can appear in any body,usually self-limited and benign. Extravesical forms evidencea more aggressive course. Diagnostic is done through histopatology, being Michaelis-Guttmann bodiespathognomonic. It is associated to chronic conditions, systemic diseases, immune depression and neoplasia. Medical treatment is non-specific and in the case of voluminous masses surgery is recommended. Prognosis is closelyrelated to the localization of the process and the present of concomitant diseases.The malakoplakia case reported is unusual given its clinical presentation (repeated high digestive hemorrhage),the topographical origin, lymph node commitment and the dissemination of the condition, as well as its malignevolution.

A malacoplaquia é uma doença granulomatosa crônica que afeta principalmente o trato geniturinário embora possa se desenvolver em outros órgãos; geralmente é autolimitada e benigna. As formas extravesicais são mais agressivas. O diagnósticoé histopatológico, sendo patognomônicos os corpos de Michaelis-Guttmann. Está vinculada a infecções crônicas, doenças sistêmicas, imunodepressão e neoplasmas.O tratamento médico é inespecífico e quando se observam massas voluminosas se indica cirurgia. O prognóstico está estreitamente relacionado à localização do processo e a presença de doenças concomitantes.O caso de malacoplaquia que se descreve apresenta características excepcionais pelo quadro clínico (HDA repetidas), por sua origem topográfica, o compromisso ganglionar e a disseminação, como também pela evolução maligna.

Assessment of tumoricidal efficacy and response to treatment with 18F-FDG PET/CT after intraarterial infusion with the antiglycolytic agent 3-bromopyruvate in the VX2 model of liver tumor.

UNLABELLED: The purpose of this study was to determine the effects of 3-bromopyruvate (3-BrPA) on tumor glucose metabolism as imaged with (18)F-FDG PET/CT at multiple time points after treatment and compare them with those after intraarterial control injections of saline. METHODS: Twenty-three New Zealand White rabbits implanted intrahepatically with VX2 tumors were assigned to 1 of 2 groups: 14 rabbits were assigned to the treatment group (TG) and 9 to the saline control group (SG). All animals were infused with 25 mL of either 1.75 mM 3-BrPA or saline over 1 h via a 2-French catheter, which was secured in the hepatic artery. For PET/CT, the animals were injected with 37 MBq of (18)F-FDG at 1 d before treatment and 2 h, 24 h, and 1 wk after treatment. Tumor size, tumor and liver maximal standardized uptake value (SUV(max)), and tumor-to-background ratios were calculated for all studies. Seven TG and 5 SG animals were sacrificed at 1 wk after treatment for histopathologic analysis. RESULTS: Intense (18)F-FDG uptake was seen in untreated tumors. A significant reduction in tumor SUV(max) was noted in TG animals, when compared with SG animals, at 1 wk after treatment (P = 0.006). The tumor-to-liver background ratio in the TG animals, compared with the SG animals, was significantly reduced as early as 24 h after treatment (P = 0.01) and remained reduced at 1 wk (P = 0.003). Tumor SUV(max) increased from the baseline levels at 7 d in controls (P = 0.05). The histopathologic analysis of explanted livers revealed increased tumor necrosis in all TG samples. There was a significant inverse correlation (r(2) = 0.538, P = 0.005) between the percentage of tumor necrosis on histopathology and tumor SUV(max) on (18)F-FDG PET at 7 d after treatment with 3-BrPA. CONCLUSION: Intraarterial injection of 3-BrPA resulted in markedly decreased (18)F-FDG uptake as imaged by PET/CT and increased tumor necrosis on histopathology at 1 wk after treatment in the VX2 rabbit liver tumor. PET/CT appears to be a useful means to follow antiglycolytic therapy with 3-BrPA.

Doxorubicin-loaded QuadraSphere microspheres: plasma pharmacokinetics and intratumoral drug concentration in an animal model of liver cancer.

The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

Diffusion-weighted and Gd-EOB-DTPA-contrast-enhanced magnetic resonance imaging for characterization of tumor necrosis in an animal model.

PURPOSE: To evaluate the role of diffusion-weighted magnetic resonance imaging (MRI) in determining tumor necrosis and contrast-enhanced MRI using gadoxetic acid disodium (Gd-EOB-DTPA) in determining maximum tumor size measurement and tumor delineation compared with criterion-standard histologic measurements in the rabbit VX2 liver tumor model. MATERIALS AND METHODS: VX2 tumors were implanted in the livers of 13 rabbits. Magnetic resonance imaging was performed using a 1.5-T MRI scanner and an extremity coil. The imaging protocol included T2-weighted fast spin-echo images, 3-dimensional T1-weighted spoiled gradient-echo with and without fat suppression after administration of Gd-EOB-DTPA, and diffusion-weighted echo planar images. Rabbits were killed, and the tumor was harvested and sliced at 4-mm intervals in the axial plane. The MRI parameters evaluated were tumor size, tumor delineation, and tumor apparent diffusion coefficient (ADC) values. Histologic sections were evaluated to quantify tumor necrosis. RESULTS: On contrast-enhanced MRI (obtained from 11 rabbits), the mean tumor sizes were 20, 19, and 20 mm in the arterial, portal venous, and delayed phases, respectively. Tumor delineation was most distinguishable in the delayed phase. On diffusion-weighted MRI (acquired in 13 rabbits), the mean tumor ADC value was 1.84 x 10 mm/s. The mean tumor size at pathology was 16 mm. The mean percent necrosis at the tumor's pathologic condition was 36%. The correlation between ADC value and percent necrosis showed an R value of 0.68. CONCLUSIONS: Contrast-enhanced MRI using Gd-EOB-DTPA may provide additional information about tumor outline in the liver. Moreover, we showed a remarkable correlation between ADC values and tumor necrosis. Thus, diffusion-weighted imaging may be useful to assess tumor necrosis; nevertheless, the search for new modalities remains important.

Percutaneous US-guided implantation of Vx-2 carcinoma into rabbit liver: a comparison with open surgical method.

PURPOSE: To evaluate technical feasibility and experimental usefulness of percutaneous US-guided implantation of Vx-2 carcinoma in rabbit liver. MATERIALS AND METHODS: Forty-eight New Zealand White male rabbits were used. Solid tumor mass of Vx-2 carcinoma was harvested from carrier rabbit, and minced tumor cells were implanted. Twenty-four rabbits underwent percutaneous US-guided tumor implantation, and the same number of rabbits underwent open laparotomy tumor implantation. Tested parameters included technical success, procedural time, amount of anesthesia, recovery time, complications, tumor size, and regional tumor seeding. RESULTS: A new percutaneous US-guided implantation was technically feasible in all rabbits. Evaluation parameters showed that the percutaneous US-guided implantation method is less invasive than the open laparotomy method. Targeting rate for left lateral lobe of implantation site was comparable in both methods (91.7% of percutaneous US-guided; 95.8% in open laparotomy). The success rate of tumor growth in the liver was 100% in both groups. However, in the group with US-guidance, tumor seeding developed more frequently in five of 24 rabbits (20.8%) than in open laparotomy group (2/24, 8.3%). Five rabbits had thoracoabdominal wall needle tract seeding, and two rabbits had tumor seeding at both thoracoabdominal wall and intraperitoneal space. CONCLUSIONS: Percutaneous US-guided implantation of Vx-2 carcinoma in rabbit liver is a less invasive alternative to open laparotomy, achieving equally successful tumor growth in the liver. Although percutaneous US-guidance implantation method may not be considered for long-term survival study design because of the possibility of tumor seeding, it can be considered for nonsurvival study design.

Distribution of iron oxide-containing Embosphere particles after transcatheter arterial embolization in an animal model of liver cancer: evaluation with MR imaging and implication for therapy.

PURPOSE: To test whether different-sized iron oxide-containing Embosphere (IOE) particles can be detected by dedicated magnetic resonance (MR) imaging when injected intraarterially in an animal model of liver cancer and whether their distribution could be accurately predicted by MR imaging before confirmation with histopathologic analysis. MATERIALS AND METHODS: Twenty New Zealand White rabbits implanted with VX2 liver tumor were randomly assigned to undergo embolization with 100-300-microm particles (group S; n = 10) or 300-500-microm particles (group L; n = 10). Embolization was performed with the catheter placed in the proper hepatic artery. T2*-weighted multiplanar MR imaging was performed within 24 hours after the procedure to detect paramagnetic IOE susceptibility artifact. MR imaging interpretation parameters included presence of artifact in the artery and/or at the tumor bed. Hematoxylin and eosin- and Prussian blue-stained pathologic slides were also obtained and the presence of IOE was evaluated similarly. RESULTS: The MR detectability rates for IOEs were 100% in both groups. Paramagnetic susceptibility IOE artifact inside the tumor was detected in 30% of group S animals. On pathologic analysis, IOE particles were detected inside the tumor in 70% of this group. IOEs in group L were found outside the tumor within the hepatic artery on MR imaging and histopathologic study (P < .05). CONCLUSIONS: MR imaging readily detected IOE particles in an animal model of liver cancer regardless of the particle size. The smaller particles (100-300 microm) were delivered inside the tumor or in close proximity to the tumor margin, justifying their use for drug delivery or precise embolization.

Targeting of VX2 rabbit liver tumor by selective delivery of 3-bromopyruvate: a biodistribution and survival study.

The aim of this study was to determine the biodistribution and tumor targeting ability of (14)C-labeled 3-bromopyruvate ([(14)C]3-BrPA) after i.a. and i.v. delivery in the VX2 rabbit model. In addition, we evaluated the effects of [(14)C]3-BrPA on tumor and healthy tissue glucose metabolism by determining (18)F-deoxyglucose (FDG) uptake. Last, we determined the survival benefit of i.a. administered 3-BrPA. In total, 60 rabbits with VX2 liver tumor received either 1.75 mM [(14)C]3-BrPA i.a., 1.75 mM [(14)C]3-BrPA i.v., 20 mM [(14)C]3-BrPA i.v., or 25 ml of phosphate-buffered saline (PBS). All rabbits (with the exception of the 20 mM i.v. group) received FDG 1 h before sacrifice. Next, we compared survival of animals treated with i.a. administered 1.75 mM [(14)C]3-BrPA in 25 ml of PBS (n = 22) with controls (n = 10). After i.a. infusion, tumor uptake of [(14)C]3-BrPA was 1.8 +/- 0.2% percentage of injected dose per gram of tissue (%ID/g), whereas other tissues showed minimal uptake. After i.v. infusion (1.75 mM), tumor uptake of [(14)C]3-BrPA was 0.03 +/- 0.01% ID/g. After i.a. administration of [(14)C]3-BrPA, tumor uptake of FDG was 26 times lower than in controls. After i.v. administration of [(14)C]3-BrPA, there was no significant difference in tumor FDG uptake. Survival analysis showed that rabbits treated with 1.75 mM 3-BrPA survived longer (55 days) than controls (18.6 days). Intra-arterially delivered 3-BrPA has a favorable biodistribution profile, combining a high tumor uptake resulting in blockage of FDG uptake with no effects on healthy tissue. The local control of the liver tumor by 3-BrPA resulted in a significant survival benefit.

Evaluation of different calibrated spherical polyvinyl alcohol microspheres in transcatheter arterial chemoembolization: VX2 tumor model in rabbit liver.

PURPOSE: To assess whether porosity and compressibility of calibrated spherical polyvinyl alcohol (PVA) microspheres affect doxorubicin plasma and tumor concentrations after transcatheter arterial chemoembolization (TACE) in a VX2 rabbit model. MATERIALS AND METHODS: Fifteen rabbits were divided into three groups of five rabbits each. Three different types of calibrated spherical PVA microspheres with variable levels of porosity and compressibility were blindly evaluated. TACE was performed by injecting a mixture of doxorubicin (5 mg) and iodized oil (0.5 mL) followed by injection of the embolic material (0.3-0.5 mL). Plasma concentrations of doxorubicin and doxorubicinol were analyzed 20, 40, 60, and 120 minutes and 2 days after TACE, and liver tissue and tumor doxorubicin concentrations were measured 2 days after TACE. RESULTS: All calibrated spherical PVA microspheres showed similar patterns of plasma doxorubicin and doxorubicinol release and tumor concentration of doxorubicin. There were no significant differences of drug levels in either plasma or tumor in each group (P > .05). CONCLUSIONS: After TACE in a rabbit model of liver cancer, testing of three different types of spherical PVA microspheres with varying degrees of porosity and compressibility showed no significant differences in the plasma doxorubicin release pattern and tumor doxorubicin uptake.

Glycogen synthase kinase-3beta binds to E2F1 and regulates its transcriptional activity.

GSK3beta and E2F1 play an important role in the control of proliferation and apoptosis. Previous work has demonstrated that GSK3beta indirectly regulates E2F activity through modulation of cyclin D1 levels. In this work we show that GSK3beta phosphorylates human E2F1 in vitro at serine 403 and threonine 433, both residues localized at its transactivation domain. This phosphorylation was not detected in vivo. However, co-immunoprecipitation experiments do reveal in vivo binding of these proteins. Moreover, uninhibitable and catalitycally inactive GSK3beta forms inhibit the transcriptional activity of a fusion protein containing E2F1 transactivation domain. Both forms of GSK3beta inhibit E2F1 with similar efficiency. Interestingly the effect was independent of the mutation of serine 403 and threonine 433 to alanine. This suggests that this transcriptional modulation is independent of GSK3beta kinase activity and phosphorylation state of serine 403 and threonine 433. The re-targeting of these GSK3beta forms to the nucleus results in a higher capacity to regulate E2F1 transcriptional activity. Depletion of the levels of GSK3beta protein using siRNA activates E2F1 transcriptional activity. The data presented in this study offer a new mechanism of regulation of E2F1 by direct binding of GSK3beta to its transactivation domain.