Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma.

BACKGROUND: The current standard of care for pancreatic cancer is weekly gemcitabine administered for 3 of 4 weeks with a 1-week break between treatment cycles. Maximum tolerated dose (MTD)-driven regimens as such are often associated with toxicities. Recent studies demonstrated that frequent dosing of chemotherapeutic drugs at relatively lower doses in metronomic regimens also confers anti-tumour activity but with fewer side effects. METHODS: Herein, we evaluated the anti-tumour efficacy of metronomic vs MTD gemcitabine, and investigated their effects on the tumour microenvironment in two human pancreatic cancer xenografts established from two different patients. RESULTS: Metronomic and MTD gemcitabine significantly reduced tumour volume in both xenografts. However, K(trans) values were higher in metronomic gemcitabine-treated tumours than in their MTD-treated counterparts, suggesting better tissue perfusion in the former. These data were further supported by tumour-mapping studies showing prominent decreases in hypoxia after metronomic gemcitabine treatment. Metronomic gemcitabine also significantly increased apoptosis in cancer-associated fibroblasts and induced greater reductions in the tumour levels of multiple pro-angiogenic factors, including EGF, IL-1alpha, IL-8, ICAM-1, and VCAM-1. CONCLUSION: Metronomic dosing of gemcitabine is active in pancreatic cancer and is accompanied by pronounced changes in the tumour microenvironment.

Dynamic contrast-enhanced MRI for prostate cancer localization.

Radiotherapy dose escalation improves tumour control in prostate cancer but with increased toxicity. Boosting focal tumour only may allow dose escalation with acceptable toxicity. Intensity-modulated radiotherapy can deliver this, but visualization of the tumour remains limiting. CT or conventional MRI techniques are poor at localizing tumour, but dynamic contrast-enhanced MRI (DCE-MRI) may be superior. 18 patients with prostate cancer had T(2) weighted (T2W) and DCE-MRI prior to prostatectomy. The prostate was sectioned meticulously so as to achieve accurate correlation between imaging and pathology. The accuracy of DCE-MRI for cancer detection was calculated by a pixel-by-pixel correlation of quantitative DCE-MRI parameter maps and pathology. In addition, a radiologist interpreted the DCE-MRI and T2W images. The location of tumour on imaging was compared with histology, and the accuracy of DCE-MRI and T2W images was then compared. Pixel-by-pixel comparison of quantitative parameter maps showed a significant difference between the benign peripheral zone and tumour for the parameters K(trans), v(e) and k(ep). Calculation of areas under the receiver operating characteristic curve showed that the pharmacokinetic parameters were only "fair" discriminators between cancer and benign gland. Interpretation of DCE-MRI and T2W images by a radiologist showed DCE-MRI to be more sensitive than T2W images for tumour localization (50% vs 21%; p = 0.006) and similarly specific (85% vs 81%; p = 0.593). The superior sensitivity of DCE-MRI compared with T2W images, together with its high specificity, is arguably sufficient for its use in guiding radiotherapy boosts in prostate cancer.

Distortion-corrected T2 weighted MRI: a novel approach to prostate radiotherapy planning.

The purpose of this study was to evaluate distortion-corrected MRI as a radiotherapy planning tool for prostate cancer and the resultant implications for dose sparing of organs at risk. 11 men who were to be treated with radical conformal radiotherapy for localized prostate cancer had an MRI scan under radiotherapy planning conditions, which was corrected for geometric distortion. Radiotherapy plans were created for planning target volumes derived from the MRI- and CT-defined prostate. Dose volume histograms were produced for the rectum, bladder and penile bulb. The mean volume of the prostate as defined on CT and MRI was 41 cm3 and 36 cm3, respectively (p = 0.009). The predicted percentage of the rectum treated to dose levels of 45-65 Gy was significantly lower for plans delineating the prostate with MRI than for those with CT. The rectal-sparing effect was confined to the lowermost 4 cm of the rectum (anal canal). There were no differences between the predicted doses to bladder or penile bulb (as defined using MRI) between plans. In conclusion, prostate radiotherapy planning based on distortion-corrected MRI is feasible and results in a smaller target volume than does CT. This leads to a lower predicted proportion of the rectum, in particular the lower rectum (anal canal), treated to a given dose than with CT.

Magnetic resonance imaging in prostate cancer: the value of apparent diffusion coefficients for identifying malignant nodules.

The aim of this work was to determine the potential of diffusion weighted magnetic resonance imaging (DW-MRI) for identifying prostate cancer by comparing apparent diffusion coefficients (ADCs) from malignant peripheral zone (PZ) nodules with values from the non-malignant PZ and the predominantly benign central gland (CG). 33 patients with elevated prostate specific antigen (PSA) aged 52-78 years (30 patients with biopsy proven prostate cancer) underwent endorectal MRI with T2 weighted and echo planar diffusion weighting (b = 0 mm2 s(-1), 300 mm2 s(-1), 500 mm2 s(-1) and 800 mm2 s(-1)) sequences. ADCs were measured from 30 malignant PZ nodules (identified on T2 weigting and positive biopsy; median region of interest (ROI) size 41 mm2), 33 CG regions (predominantly benign nodules; median ROI size 218 mm2) and 18 non-malignant PZ regions (ipsilateral biopsies all benign; median ROI size 54.5 mm2). ADCs were (mean+/-standard deviation (SD); mm2 s(-1)): malignant PZ nodules 1.30+/-0.30x10(-3), CG 1.46+/-0.14x10(-3) and non-malignant PZ 1.71+/-0.16x10(-3). Differences between all three groups were statistically significant (p = 0.01 malignant PZ vs CG; p = 0.0001 malignant PZ vs non-malignant PZ and p = 0.0001 CG vs non-malignant PZ). Using receiver operating characteristic curves, cut-off values of 1.39x10(-3) mm2 s(-1) differentiated malignant PZ nodules from predominantly benign CG (sensitivity 60%, specificity 76%) and of 1.6x10(-3) mm2 s(-1) identified malignant from non-malignant PZ (sensitivity 86.7%, specificity 72.2%). These results suggest that DW-MRI has the potential to increase the specificity of prostate cancer detection because ADCs are significantly lower in malignant compared with non-malignant prostate tissue.

Processing of radical prostatectomy specimens for correlation of data from histopathological, molecular biological, and radiological studies: a new whole organ technique.

AIMS: To develop a method of processing non-formalin fixed prostate specimens removed at radical prostatectomy to obtain fresh tissue for research and for correlating diagnostic and molecular results with preoperative imaging. METHODS/RESULTS: The method involves a prostate slicing apparatus comprising a tissue slicer with a series of juxtaposed planar stainless steel blades linked to a support, and a cradle adapted to grip the tissue sample and receive the blades. The fresh prostate gland is held in the cradle and the blades are moved through the cradle slits to produce multiple 4 mm slices of the gland in a plane perpendicular to its posterior surface. One of the resulting slices is preserved in RNAlater. The areas comprising tumour and normal glands within this preserved slice can be identified by matching it to the haematoxylin and eosin stained sections of the adjacent slices that are formalin fixed and paraffin wax embedded. Intact RNA can be extracted from the identified tumour and normal glands within the RNAlater preserved slice. Preoperative imaging studies are acquired with the angulation of axial images chosen to be similar to the slicing axis, such that stained sections from the formalin fixed, paraffin wax embedded slices match their counterparts on imaging. CONCLUSIONS: A novel method of sampling fresh prostate removed at radical prostatectomy that allows tissue samples to be used both for diagnosis and molecular analysis is described. This method also allows the integration of preoperative imaging data with histopathological and molecular data obtained from the prostate tissue slices.