Tristan Barrett

Dynamic Contrast-Enhanced MRI of Prostate Cancer at 3 T: A Study of Pharmacokinetic Parameters

OBJECTIVE The objectives of our study were to determine whether dynamic contrast-enhanced MRI performed at 3 T and analyzed using a pharmacokinetic model improves the diagnostic performance of MRI for the detection of prostate cancer compared with conventional T2-weighted imaging, and to determine which pharmacokinetic parameters are useful in diagnosing prostate cancer. SUBJECTS AND METHODS This prospective study included 50 consecutive patients with biopsy-proven prostate cancer who underwent imaging of the prostate on a 3-T scanner with a combination of a sensitivity-encoding (SENSE) cardiac coil and an endorectal coil. Scans were obtained at least 5 weeks after biopsy. T2-weighted turbo spin-echo images were obtained in three planes, and dynamic contrast-enhanced images were acquired during a single-dose bolus injection of gadopentetate dimeglumine (0.1 mmol/kg). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were estimated for T2-weighted and dynamic contrast-enhanced MRI. The following pharmacokinetic modeling parameters were determined and compared for cancer, inflammation, and healthy peripheral zone: K(trans) (forward volume transfer constant), k(ep) (reverse reflux rate constant between extracellular space and plasma), v(e) (the fractional volume of extracellular space per unit volume of tissue), and the area under the gadolinium concentration curve (AUGC) in the first 90 seconds after injection. RESULTS Pathologically confirmed cancers in the peripheral zone of the prostate were characterized by their low signal intensity on T2-weighted scans and by their early enhancement, early washout, or both on dynamic contrast-enhanced MR images. The overall sensitivity, specificity, PPV, and NPV of T2-weighted imaging were 94%, 37%, 50%, and 89%, respectively. The sensitivity, specificity, PPV, and NPV of dynamic contrast-enhanced MRI were 73%, 88%, 75%, and 75%, respectively. K(trans), k(ep), and AUGC were significantly higher (p < 0.001) in cancer than in normal peripheral zone. The ve parameter was not significantly associated with prostate cancer. CONCLUSION MRI of the prostate performed at 3 T using an endorectal coil produces high-quality T2-weighted images; however, specificity for prostate cancer is improved by also performing dynamic contrast-enhanced MRI and using pharmacokinetic parameters, particularly K(trans) and k(ep), for analysis. These results are comparable to published results at 1.5 T.

In vivo Diagnosis of Epidermal Growth Factor Receptor Expression using Molecular Imaging with a Cocktail of Optically Labeled Monoclonal Antibodies

Purpose: Epidermal growth factor receptors (EGFR) play an important role in tumorigenesis and, therefore, have become targets for new molecular therapies. Here, we use a “cocktail” of optically labeled monoclonal antibodies directed against EGFR-1 (HER1) and EGFR-2 (HER2) to distinguish tumors by their cell surface expression profiles. Experimental Design:In vivo imaging experiments were done in tumor-bearing mice following s.c. injection of A431 (overexpressing HER1), NIH3T3/HER2+ (overexpressing HER2), and Balb3T3/DsRed (non-expression control) cell lines. After tumor establishment, a cocktail of optically labeled antibodies: Cy5.5-labeled cetuximab (anti-HER1) and Cy7-labeled trastuzumab (anti-HER2) was i.v. injected. In vivo and ex vivo fluorescence imaging was done. For comparison with radionuclide imaging, experiments were undertaken using 111Indium-labeled antibodies. Additionally, a “blinded” diagnostic study was done for mice bearing one tumor type. Results:In vivo spectral fluorescent molecular imaging of 14 mice with three tumor types clearly differentiated tumors using the cocktail of optically labeled antibodies both in vivo and ex vivo. Twenty-four hours after injection, A431 and NIH3T3/HER2+ tumors were detected distinctly by their peak on Cy5.5 and Cy7 spectral images, respectively; radionuclide imaging was unable to clearly distinguish tumors at this time point. In blinded single tumor experiments, investigators were able to correctly diagnose a total of 40 tumors. Conclusion: An in vivo imaging technique using an antibody cocktail simultaneously differentiated two tumors expressing distinct EGFRs and enabled an accurate characterization of each subtype.

Value of the Hemorrhage Exclusion Sign on T1-weighted Prostate MR Images for the Detection of Prostate Cancer

PURPOSE To retrospectively determine the prevalence and positive predictive value (PPV) of the hemorrhage exclusion sign on T1-weighted magnetic resonance (MR) images in conjunction with findings on T2-weighted images in the detection of prostate cancer, with use of whole-mount step-section pathologic specimens from prostatectomy as the reference standard. MATERIALS AND METHODS The institutional review board approved this retrospective study, which was compliant with HIPAA, and the requirement to obtain informed consent was waived. Two hundred ninety-two patients with biopsy-proved prostate cancer underwent endorectal MR imaging followed by prostatectomy. The hemorrhage exclusion sign was defined as the presence of a well-defined area of low signal intensity surrounded by areas of high signal intensity on T1-weighted images. Two readers independently assessed the presence and extent of postbiopsy changes and the hemorrhage exclusion sign. The presence of a corresponding area of homogeneous low signal intensity on T2-weighted images was also recorded. The prevalence and PPV of the hemorrhage exclusion sign were calculated. RESULTS Readers 1 and 2 found postbiopsy changes in the peripheral zone in 184 (63%) and 189 (64.7%) of the 292 patients, respectively. In these patients, the hemorrhage exclusion sign was observed in 39 of 184 patients (21.2%) by reader 1 and 36 of 189 patients (19.0%) by reader 2. A corresponding area of homogeneous low signal intensity was seen on T2-weighted images in the same location as the hemorrhage exclusion sign in 23 of 39 patients (59%) by reader 1 and 19 of 36 patients (53%) by reader 2. The PPV of the hemorrhage exclusion sign alone was 56% (22 of 39 patients) for reader 1 and 50% (18 of 36 patients) for reader 2 but increased to 96% (22 of 23 patients) and 95% (18 of 19 patients) when the sign was identified in an area of homogeneous low signal intensity on T2-weighted images. CONCLUSION Postbiopsy change is a known pitfall in the interpretation of T2-weighted images. The authors have shown that a potential benefit of postbiopsy change is the presence of excluded hemorrhage, which, in conjunction with a corresponding area of homogeneous low signal intensity at T2-weighted imaging, is highly accurate for cancer identification.

Radiological staging in breast cancer: which asymptomatic patients to image and how

Background:Approximately 4% of patients diagnosed with early breast cancer have occult metastases at presentation. Current national and international guidelines lack consensus on whom to image and how.Methods:We assessed practice in baseline radiological staging against local guidelines for asymptomatic newly diagnosed breast cancer patients presenting to the Cambridge Breast Unit over a 9-year period.Results:A total of 2612 patients were eligible for analysis; 91.7% were appropriately investigated. However in the subset of lymph node negative stage II patients, only 269 out of 354 (76.0%) investigations were appropriate. No patients with stage 0 or I disease had metastases; only two patients (0.3%) with stage II and ⩽3 positive lymph nodes had metastases. Conversely, 2.2, 2.6 and 3.8% of these groups had false-positive results. The incidence of occult metastases increased by stage, being present in 6, 13.9 and 57% of patients with stage II (⩾4 positive lymph nodes), III and IV disease, respectively.Conclusion:These results prompted us to propose new local guidelines for staging asymptomatic breast cancer patients: only clinical stage III or IV patients require baseline investigation. The high specificity and convenience of computed tomography (chest, abdomen and pelvis) led us to recommend this as the investigation of choice in breast cancer patients requiring radiological staging.

Multi-excitation near infrared (NIR) spectral fluorescence imaging using organic fluorophores

The ability to obtain multi-color fluorescent imaging in vivo simultaneously using multi-targeted imaging probes could be of potential benefit from both a research and a clinical perspective. However, the simultaneous acquisition of more than 2 separate organic fluorophores usually requires more than one excitation source, since a single excitation source may not optimally excite all the fluorophores. In this study, we employed a multi-excitation approach in order to acquire optimized images with multiple near infrared (NIR) organic fluorophores at the same time. Using 3 sets of excitation filters (595±20nm, 640±25nm, 688±17nm) to acquire 3 distinct spectra and spectral unmixing software (CRi, Woburn, MA), it was possible to resolve the emission spectra of each of the NIR fluorophores using commercial software (Nuance, CRi, Woburn, MA) To demonstrate the utility of this approach 2 mouse models were investigated; In one model, mice bearing four implanted malignancies were injected with a cocktail of 3 fluorescently labeled monoclonal antibodies, each with its own distinct NIR fluorophore. In the second model five different lymph node drainage basins were imaged with 5-color dendrimer-based lymphatic imaging agents tagged with 5 different NIR fluorophores. We successfully detected each of the targeted tumors in the first model and all of the lymph nodes by their distinct color in the second model; neither of which would have been possible using the single excitation method. In conclusion, multi-excitation NIR spectral fluorescence imaging is feasible in a reasonable time frame and opens the possibility for in vivo immunohistochemical imaging (IHCi).

Whole-body multicolor spectrally resolved fluorescence imaging for development of target-specific optical contrast agents using genetically engineered probes

Target-specific contrast agents are being developed for the molecular imaging of cancer. Optically detectable target-specific agents are promising for clinical applications because of their high sensitivity and specificity. Pre clinical testing is needed, however, to validate the actual sensitivity and specificity of these agents in animal models, and involves both conventional histology and immunohistochemistry, which requires large numbers of animals and samples with costly handling. However, a superior validation tool takes advantage of genetic engineering technology whereby cell lines are transfected with genes that induce the target cell to produce fluorescent proteins with characteristic emission spectra thus, identifying them as cancer cells. Multicolor fluorescence imaging of these genetically engineered probes can provide rapid validation of newly developed exogenous probes that fluoresce at different wavelengths. For example, the plasmid containing the gene encoding red fluorescent protein (RFP) was transfected into cell lines previously developed to either express or not-express specific cell surface receptors. Various antibody-based or receptor ligand-based optical contrast agents with either green or near infrared fluorophores were developed to concurrently target and validate cancer cells and their positive and negative controls, such as &bgr;-D-galactose receptor, HER1 and HER2 in a single animal/organ. Spectrally resolved fluorescence multicolor imaging was used to detect separate fluorescent emission spectra from the exogenous agents and RFP. Therefore, using this in vivo imaging technique, we were able to demonstrate the sensitivity and specificity of the target-specific optical contrast agents, thus reducing the number of animals needed to conduct these experiments.