A brief history of long circulating nanoparticles.

The propensity of the hepatic macrophages (Kupffer cells) to rapidly intercept particulate materials from the blood has been frustrating in redirecting intravenously injected nanomedicines to pathological sites in sufficient quantities to exert appropriate pharmacological effect. The development of long circulating nanoparticles has offered unprecedented opportunities for controlled drug release within vasculature and for drug delivery to sites other than Kupffer cells. These developments were based on mechanistic understanding of complex and integrated body's defences against intruders as well as translation of protective strategies developed by the body's own cells and virulent pathogens against immune attack. Thanks to interdisciplinary and integrated approaches, numerous organic and inorganic nanoparticles with long circulating properties have become available. By long circulation we mean particles that remain in the blood for periods of hours rather than minutes, but blood longevity must be tuned in accordance with therapeutic needs. Here, we provide a brief history of these efforts and highlight important lessons learned in camouflaging nanoparticles with strategies that avoid rapid interception by Kupffer cells.

Traumatic diaphragmatic hernia: delayed presentation with tension viscerothorax--lessons to learn.

Diaphragmatic rupture is a serious complication of thoracoabdominal trauma. The condition may be missed initially. We describe the clinical course of a patient who sustained blunt abdominal trauma in a car accident. His diaphragmatic injury passed unnoticed, to present two years later with left tension viscerothorax, a rarely reported and hardly recognised entity. Nasogastric tube insertion aborted the emergency situation and the hernia was repaired successfully in a semielective setting.

Comparison of cerebral blood volume maps generated from T2* and T1 weighted MRI data in intra-axial cerebral tumours.

We compared parametric maps, measured values and value distributions of cerebral blood volume (CBV) derived from (1) first pass T1 weighted dynamic contrast-enhanced (DCE) data (T1-CBV) using the recently described leakage profile model and (2) conventional T2* weighted DCE data (T2*-CBV) using a conventional curve fitting technique, in nine patients with intraaxial tumours. Regions of interest were defined around enhancing tumour tissue on matched slices. Median tumour values and conspicuity indexes of CBV from the two techniques were compared, demonstrating good correlation (r = 0.667,p<0.05) in enhancing tumour and no significant difference in conspicuity. Pixel-by-pixel scattergrams of values in normal brain in a representative matched slice were produced for each case, which showed excellent correlation (r = 0.96,p<0.001). Distortion of blood vessels around susceptibility interfaces was evident on T2* CBV but not on T1 CBV maps. Leakage-free T1 CBV maps do not suffer from the susceptibility artifacts seen in T2* CBV maps, although they present comparable biological information.

Do cerebral blood volume and contrast transfer coefficient predict prognosis in human glioma?

INTRODUCTION: Noninvasive measurements of cerebral blood volume (CBV) and contrast transfer coefficient (K(trans)) have potential benefits in the diagnosis and therapeutic management of adult glioma. This study examines the relationship between CBV, K(trans), and overall survival. METHODS AND MATERIALS: Twenty-seven adult patients with glioma underwent T1-weighted dynamic contrast-enhanced MR imaging, and parametric maps of CBV and K(trans) were calculated. The relationship of histologic grade, CBV, K(trans), age, sex, surgical resection, and use of adjuvant therapy to survival were analyzed by using the logrank method and Cox regression analysis. The Kaplan-Meier method for displaying survival curves was used. The relationship of factors such as comorbidity, elevated intracranial pressure, size of nonenhancing tumor, and peritumoral edema were not considered. RESULTS: Both CBV (P < .01) and K(trans) (P < .01) show a significant relationship to histologic grade. CBV (P = .004), K(trans) (P = .008), and histologic grade (P < .001) all demonstrate a significant association with patient survival when analyzed individually. Cox regression analysis identified only histologic grade (P < .01) and K(trans) (P < .05) as independent significant prognostic indicators. Examination of survival data from high-grade (III and IV) tumors demonstrated a linear relationship between K(trans) and patient survival (P < .01). CONCLUSION: This study suggests a direct relationship between K(trans) and length of survival in high-grade gliomas, which could be of clinical importance. CBV relates directly to histologic grade but provides no independent prognostic information over and above that provided by grade. Further large prospective studies should be planned to test whether this observation holds true.

Breath-hold perfusion and permeability mapping of hepatic malignancies using magnetic resonance imaging and a first-pass leakage profile model.

We have applied a novel pharmacokinetic model of the distribution of contrast media to dynamic contrast-enhanced MRI data from patients with hepatic neoplasms. The model uses data collected during the passage of a bolus of contrast medium and allows breath-hold image acquisition. The aims of the study were to investigate the feasibility of permeability mapping using the first pass technique and breath-hold acquisitions, and to examine the reproducibility of the technique and the effect of the liver's dual vascular supply on the assumptions of the model. Imaging was performed in 14 patients with hepatic neoplasms. Dynamic data clearly demonstrated differences in the timing and shape of the contrast medium concentration-time course curve in the systemic arterial and portal venous systems. Mapping of the arrival time (T(0)) of contrast medium allowed identification of tissue supplied by the hepatic arteries and portal vein. Hepatic tumours all showed typical hepatic arterial enhancement. Repeated measurements of endothelial permeability surface area product (k(fp)) and relative blood volume (rBV), performed in five patients, showed excellent reproducibility with variance ratios (V(r)) of 0.134 and 0.113, respectively. Measurement of enhancing tumour volume was also highly reproducible (V(r) = 0.096) and this was further improved by the use of T(0) maps to identify pixels supplied by the hepatic artery (V(r) = 0.026). Estimates of k(fp) and rBV in normal hepatic tissue supplied by the portal vein were highly inaccurate and these pixels were identified by use of the T(0) parameter and excluded from the analysis. In conclusion, dynamic MRI contrast enhancement combined with a pharmacokinetic model of the distribution of contrast media in the first pass allows us to produce highly reproducible parametric maps of k(fp) and rBV from hepatic tumours that are supplied by the hepatic arterial system using breath-hold acquisitions.