Andrew Jackson

The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations

Vascular and angiogenic processes provide an important target for novel cancer therapeutics. Dynamic contrast-enhanced magnetic resonance imaging is being used increasingly to noninvasively monitor the action of these therapeutics in early-stage clinical trials. This publication reports the outcome of a workshop that considered the methodology and design of magnetic resonance studies, recommending how this new tool might best be used.

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.

Incidental findings found in “healthy” volunteers during imaging performed for research: current legal and ethical implications

Incidental findings found in healthy volunteers during research imaging are common and have important implications for study design and performance, particularly in the areas of informed consent, subjects rights, clinical image analysis and disclosure. In this study, we aimed to determine current practice and regulations concerning information that should be given to research subjects when obtaining consent, reporting of research images, who should be informed about any incidental findings and the method of disclosure. We reviewed all UK, European and international humanitarian, legal and ethical agencies guidance. We found that the guidance on what constitutes incidental pathology, how to recognise it and what to do about it is inconsistent between agencies, difficult to find and less complete in the UK than elsewhere. Where given, guidance states that volunteers should be informed during the consent process about how research images will be managed, whether a mechanism exists for identifying incidental findings, arrangements for their disclosure, the potential benefit or harm and therapeutic options. The effects of incidentally discovered pathology on the individual can be complex and far-reaching. Radiologist involvement in analysis of research images varies widely; many incidental findings might therefore go unrecognised. In conclusion, guidance on the management of research imaging is inconsistent, limited and does not address the interests of volunteers. Improved standards to guide management of research images and incidental findings are urgently required.

Correlation of diffusion-weighted MRI with whole mount radical prostatectomy specimens

The purpose of this study was to compare the apparent diffusion coefficient (ADC) of benign central gland (bCG), benign peripheral zone (bPZ) and cancer using diffusion-weighted MRI and whole mount specimens. 11 patients with biopsy-proven prostate cancer underwent diffusion-weighted MRI prior to radical prostatectomy. A single-shot echo planar image technique was used with b-values of 0 s mm(-2), 300 s mm(-2), 500 s mm(-2) and 800 s mm(-2). Whole mount specimens were compared with ADC maps. Areas of cancer, bCG and bPZ were identified, and regions of interest were drawn on ADC maps. Mean ADC values were recorded for all regions of interest, and paired t-tests were performed to compare mean values. Cancer was outlined in nine patients. In two patients, the tumours were too small to correlate with images; bCG was identified in 11 patients and bPZ was identified in 10 patients. Mean ADC values for bCG, bPZ and cancer were, 1.5 x 10(-3) mm(2) s(-1) (standard error (SE) = 0.04), 1.7 x 10(-3) mm(2) s(-1) (SE = 0.1), and 1.3 x 10(-3) mm(2) s(-1) (SE = 0.09), respectively. The most significant difference between benign tissue and cancer existed at b-values of 0-300 s mm(-2) (bCG vs cancer: mean difference = 0. 29, p = 0.001, 95% confidence interval (CI) = 0.17-0.41; bPZ vs cancer: mean difference = 0.34, p = 0.003, 95% CI = 0.18-0.61). In conclusion, we have confirmed, using whole mount verification, a significant difference in the ADC between benign tissue and cancer.

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 RNAlaterTM. 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.

Management of incidental findings during imaging research in "healthy" volunteers: current UK practice

OBJECTIVESnIncidental findings (IF) are becoming increasingly common due to the proliferation of imaging research. IFs can be life-changing for healthy volunteers. This study examined variation in IF management in UK research studies of healthy volunteers, including comparison with ethical and legal guidelines, thus providing baseline data and informing future practice.nnnMETHODSnQuestionnaire of participant background [medical/non-medical; radiologist/non-radiologist; years as principal investigator (PI)], type of research (involving children or not), institutional policy, volunteer information, radiologist involvement in reporting scans and IF disclosure mechanisms. Investigators current and perceived ideal practice was examined. Participants were PIs performing imaging research of healthy volunteers approved by UK ethics committees (2006-2009).nnnRESULTSn63/146 (43%) surveys completed. 54/61 (88.5%) had site-specific guidelines. Information commonly provided to volunteers should IF be found: personal data (51/62; 82%), contingency plans (54/62; 87%) and disclosure to general practitioner (GP)/treating physician (47/62; 76%). PIs used different strategies for image review. Commonest: radiologist reports research scans only when researcher suspicious of IF [15/57 (26%) compared with 5/28 (16%) in ideal practice]. Commonest ideal reporting strategy: routine reporting by specialist radiologists [9/28 (29%) compared with 8/57 (14%) in current practice]. 49/56 (87.5%) have a standardised disclosure contingency plan, usually involving GP. PIs most commonly disclosed IFs to volunteers when judged relevant (27/58; 47%), most commonly face to face (22/54; 41%), by volunteers GP (26/60; 43%). Background of PI influenced consent, reporting and disclosure practice.nnnCONCLUSIONnThere is wide variation in handling IFs in UK imaging research. Much of the current practice contravenes the vague existing legal and ethical guidelines, and is unlikely to be in the best interests of volunteers or researchers.