Dynamic Contrast-Enhanced MRI Using a Macromolecular MR Contrast Agent (P792): Evaluation of Antivascular Drug Effect in a Rabbit VX2 Liver Tumor Model

OBJECTIVE: To evaluate the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using macromolecular contrast agent (P792) for assessment of vascular disrupting drug effect in rabbit VX2 liver tumor models. MATERIALS AND METHODS: This study was approved by our Institutional Animal Care and Use Committee. DCE-MRI was performed with 3-T scanner in 13 VX2 liver tumor-bearing rabbits, before, 4 hours after, and 24 hours after administration of vascular disrupting agent (VDA), using gadomelitol (P792, n = 7) or low molecular weight contrast agent (gadoterate meglumine [Gd-DOTA], n = 6). P792 was injected at a of dose 0.05 mmol/kg, while that of Gd-DOTA was 0.2 mmol/kg. DCE-MRI parameters including volume transfer coefficient (K(trans)) and initial area under the gadolinium concentration-time curve until 60 seconds (iAUC) of tumors were compared between the 2 groups at each time point. DCE-MRI parameters were correlated with tumor histopathology. Reproducibility in measurement of DCE-MRI parameters and image quality of source MR were compared between groups. RESULTS: P792 group showed a more prominent decrease in K(trans) and iAUC at 4 hours and 24 hours, as compared to the Gd-DOTA group. Changes in DCE-MRI parameters showed a weak correlation with histologic parameters (necrotic fraction and microvessel density) in both groups. Reproducibility of DCE-MRI parameters and overall image quality was not significantly better in the P792 group, as compared to the Gd-DOTA group. CONCLUSION: Dynamic contrast-enhanced magnetic resonance imaging using a macromolecular contrast agent shows changes of hepatic perfusion more clearly after administration of the VDA. Gadolinium was required at smaller doses than a low molecular contrast agent.

Hepatotrophic factors reduce hepatic fibrosis in rats / Fatores hepatotróficos reduzem a fibrose hepática em ratos

CONTEXT: Hepatic fibrosis occurs in response to several aggressive agents and is a predisposing factor in cirrhosis. Hepatotrophic factors were shown to stimulate liver growth and to restore the histological architecture of the liver. They also cause an improvement in liver function and accelerate the reversion of fibrosis before it progresses to cirrhosis. OBJECTIVE: To test the effects of hepatic fibrosis solution composed by amino acids, vitamins, glucose, insulin, glucagon and triiodothyronine on hepatic fibrosis in rats. METHODS: Fibrosis was induced in rats by gastric administration of dimethylnitrosamine (10 mg/kg) for 5 weeks. After liver biopsy, the rats received either hepatotrophic factors solution (40 mg/kg/day) or saline solution for 10 days by intraperitoneal injection. Blood samples and liver fragments were collected for hepatic function analysis, standard histopathology evaluation, and morphometric collagen quantification. RESULTS: Rats in the hepatotrophic factors group showed a decrease of the histopathological components of fibrosis and an increase of their hepatic mass (12.2 percent). There was no development of neoplasic lesions in both groups. Compared with the saline group, the hepatotrophic factors group also had a decrease of blood levels of hepatic-lesion markers (AST, ALT) and a decrease of collagen content in the portal spaces (31.6 percent) and perisinusoidal spaces (42.3 percent), as well as around the hepatic terminal vein (57.7 percent). Thus, hepatotrophic factors administration in the portal blood promoted a regenerative hepatic response, with an overall reduction of the volumetric density of collagen, improved hepatic function, and a general improvement in the histopathological aspects of fibrosis. CONCLUSION: Taken together, these results suggest the potential therapeutic use of this hepatotrophic factors solution to treat chronic liver diseases.

CONTEXTO: A fibrose hepática ocorre em resposta a diversos agentes agressores e é um fator predisponente da cirrose. Fatores hepatotróficos são conhecidos por estimular o crescimento hepático e restaurar a arquitetura histológica do fígado. Promovem, também, melhora na função hepática e aceleram a reversão da fibrose antes de sua progressão para cirrose. OBJETIVO: Testar os efeitos de uma solução de fatores hepatotróficos, composta por aminoácidos, vitaminas, glicose, insulina, glugacon e triiodotironina na fibrose hepática em ratos. MéTODOS: No presente estudo, a fibrose foi induzida em ratos pela administração de dimetilnitrosamina (10 mg/kg) durante 5 semanas. Após a biopsia do fígado, os ratos receberam a solução de fatores hepatotróficos (40 mg/kg/dia) ou solução salina por injeção intraperitonial, durante 10 dias. Amostras sanguíneas e fragmentos do fígado foram coletados para análise da função hepática, avaliação do critério histopatológico e quantificação morfométrica do colágeno. RESULTADOS: Os ratos do grupo fatores hepatotróficos demonstraram diminuição dos componentes histopatológicos da fibrose e aumento de massa hepática (12,2 por cento). Não houve o desenvolvimento de lesões neoplásicas em ambos os grupos. Comparado com o grupo de salina, no grupo fatores hepatotróficos também houve diminuição nos níveis dos marcadores sanguíneos de lesão hepática (AST e ALT), e diminuição da quantidade de colágeno nos espaços porta (31,6 por cento) e espaços perissinusoidais (42,3 por cento), assim como ao redor das veias terminais hepáticas (57,7 por cento). Assim, a administração de fatores hepatotróficos no sangue portal promoveu resposta regenerativa hepática, com redução da densidade volumétrica de colágeno, melhora na função hepática e melhora geral nos aspectos histopatológicos da fibrose. CONCLUSÃO: Juntos, estes resultados sugerem o potencial uso terapêutico desta solução de fatores hepatotróficos para tratar doenças hepáticas crônicas.

MR Diagnosis of a Pulmonary Embolism: Comparison of P792 and Gd-DOTA for First-Pass Perfusion MRI and Contrast-Enhanced 3D MRA in a Rabbit Model

OBJECTIVE: To compare P792 (gadomelitol, a rapid clearance blood pool MR contrast agent) with gadolinium-tetraazacyclododecanetetraacetic acid (Gd-DOTA), a standard extracellular agent, for their suitability to diagnose a pulmonary embolism (PE) during a first-pass perfusion MRI and 3D contrast-enhanced (CE) MR angiography (MRA). MATERIALS AND METHODS: A perfusion MRI or CE-MRA was performed in a rabbit PE model following the intravenous injection of a single dose of contrast agent. The time course of the pulmonary vascular and parenchymal enhancement was assessed by measuring the signal in the aorta, pulmonary artery, and lung parenchyma as a function of time to determine whether there is a significant difference between the techniques. CE-MRA studies were evaluated by their ability to depict the pulmonary vasculature and following defects between 3 seconds and 15 minutes after a triple dose intravenous injection of the contrast agents. RESULTS: The P792 and Gd-DOTA were equivalent in their ability to demonstrate PE as perfusion defects on first pass imaging. The signal from P792 was significantly higher in vasculature than that from Gd-DOTA between the first and the tenth minutes after injection. The results suggest that a CE-MRA PE could be reliably diagnosed up to 15 minutes after injection. CONCLUSION: P792 is superior to Gd-DOTA for the MR diagnosis of PE.

Early Assessment of Myocardial Contractility by Contrast-Enhanced Magnetic Resonance (ceMRI) Imaging after Revascularization in Acute Myocardial Infarction (AMI)

BACKGROUND: Recent studies have demonstrated that the size and shape of the hyperenhanced areas on contrast-enhanced magnetic resonance imaging (ceMRI) were nearly identical to areas of irreversible injury, as defined by histochemical staining. We compared the transmural extent of infarct (TEI), as defined by ceMRI, to the initial ECG findings for acute myocardial infarction (AMI), and we also assessed functional contractility according to TEI. METHODS: 12 patients who presented with their first myocardial infarction underwent cine and ceMRI 4 weeks later after their successful revascularization. TEI and wall thickening were determined by using a 30-segment model. RESULTS: Infarction was observed in 81 (23.9%) segments, of which 46 segments (56.8%) had abnormal wall motion and 35 segments (43.2%) had normal wall motion. Of the 35 segments, 33 (94.3%) had subendocardial infarction. 17 segments had infarct of less than 25% of the wall thickness, and all of them had normal wall motion. On the other hand, 11 segments had infarct of more than 75% of wall thickness, of which 11 (100%) had abnormal wall motion. None of segments with nearly transmural infarction were observed in non ST-elevation AMI. The majority of the segments with infarct had non-transmural infarction (87.5%), even if the segments were in ST-elevation AMI (76.1%). Infarct size, as defined by ceMRI, was strongly correlated with peak CK-MB and Troponin-T (r=0.96, p< 0.001, r=0.91, p< 0.001, respectively). CONCLUSION: TEI defined by ceMRI is inversely related to the contractility after revascularization in AMI. We were able to predict the future contractile function of segments with infarction using ceMRI before revascularization.

Emesis y citostáticos en el paciente pediátrico / Vomiting and cytostatic therapy in the pediatric patients

El objetivo de este estudio fue evaluar la seguridad y eficacia del ondansetron en niños con neoplasias malignas para prevenir la emesis inducida por agentes antineoplásicos con potentes efectos emetizantes. Se incluyeron 138 niños, 76 varones y 62 mujeres con tumores sólidos que cumplieron 415 ciclos de quimioterapia, desde octubre de 1993 a noviembre de 1994, en la Unidad de Administración de Citostáticos del Hospital de Pediatría "Prof. Dr. Juan P. Garrahan". Las edades oscilaron entre 1 y 17 años con una mediana de 8 para todos los grupos. Se analizaron tres tratamientos: Grupo A) 65 ciclos de quimioterapia con ifosfamida a dosis de 1.800 mg/m2/día (n=29); grupo B) 177 ciclos con ifosfamida a dosis de 3.000 mg/m2/día (n=54) y grupo C) 173 ciclos con cis-platino a dosis > 50 mg/m2/día (n=55). El antiemético utilizado fue el ondansetron a 5 mg/m2/dosis administrado por vía intravenosa cada 8 hs, durante todo el ciclo y hasta el egreso del paciente. Se obtuvo completo control de la emesis en el 69 por ciento de los ciclos en el grupo A; 54 por ciento en el grupo B y 70 por ciento en el grupo C. No se registraron reacciones adversas atribuibles al antiemético utilizado. Comparando los grupos A vs B (z: 2,225; P=0,026); B vs C (z: 3156; P=0,002), la diferencia fue significativa. En los grupos A vs C (z: 0,009; P=0,993), la diferencia no fue significativa. Conclusiones: Si bien el ondansetron resultó ser un antiemético seguro y eficaz en el control de las néuseas y vómitos agudos durante la quimioterapia, la respuesta fue menor en protocolos que incluyeron ifosfamida a 3.000 mg/m2/día, diferencia estadísticamente significativa con los otros dos grupos analizados. La dosis de este citostático influyó en la respuesta antiemética del ondansetron. Sugerimos, en función de los resultados del presente trabajo, modificar el esquema antiemético en protocolos con ifosfamida a 3.000 mg/m2/día o tal vez, prolongar la infusión de este citostático