James A. d'Arcy

Early Changes in Functional Dynamic Magnetic Resonance Imaging Predict for Pathologic Response to Neoadjuvant Chemotherapy in Primary Breast Cancer

Purpose: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows noninvasive, in vivo measurements of tissue microvessel perfusion and permeability. We examined whether DCE-MRI done after two cycles of neoadjuvant chemotherapy could predict final clinical and pathologic response in primary breast cancers. Experimental Design: Thirty-seven patients with primary breast cancer, due to receive six cycles of neoadjuvant 5-fluorouracil, epirubicin and cyclophosphamide chemotherapy, were examined using DCE-MRI before neoadjuvant chemotherapy and after two cycles of treatment. Changes in DCE-MRI kinetic parameters (Ktrans, kep, ve, MaxGd, rBV, rBF, MTT) were correlated with the final clinical and pathologic response to neoadjuvant chemotherapy. Test-retest variability was used to determine individual patient response. Results: Twenty-eight patients were evaluable for response (19 clinical responders and 9 nonresponders; 11 pathologic responders and 17 nonresponders). Changes in the DCE-MRI kinetic parameters Ktrans, kep, MaxGd, rBV, and rBF were significantly correlated with both final clinical and pathologic response (P < 0.01). Change in Ktrans was the best predictor of pathologic nonresponse (area under the receiver operating characteristic curve, 0.93; sensitivity, 94%; specificity, 82%), correctly identifying 94% of nonresponders and 73% of responders. Change in MRI-derived tumor size did not predict for pathologic response. Conclusion: Changes in breast tumor microvessel functionality as depicted by DCE-MRI early on after starting anthracycline-based neoadjuvant chemotherapy can predict final clinical and pathologic response. The ability to identify nonresponders early may allow the selection of patients who may benefit from a therapy change.

Computationally efficient vascular input function models for quantitative kinetic modelling using DCE-MRI

A description of the vascular input function is needed to obtain tissue kinetic parameter estimates from dynamic contrast enhanced MRI (DCE-MRI) data. This paper describes a general modelling framework for defining compact functional forms to describe vascular input functions. By appropriately specifying the components of this model it is possible to generate models that are realistic, and that ensure that the tissue concentration curves can be analytically calculated. This means that the computations necessary to estimate parameters from measured data are relatively efficient, which is important if such methods are to become of use in clinical practice. Three models defined by four parameters, using exponential, gamma-variate and cosine descriptions of the bolus, are described and their properties investigated using simulations. The results indicate that if there is no plasma fraction, then the proposed models are indistinguishable. When a small plasma fraction is present the exponential model gives parameter estimates that are biassed by up to 50%, while the other two models give very little bias; up to 10% but less than 5% in most cases. With a larger plasma fraction the exponential model is again biassed, the gamma-variate model has a small bias, but the cosine model has a very little bias and is indistinguishable from the model used to generate the data. The computational speed of the analytic approaches is compared with a fast-Fourier-transform-based numerical convolution approach. The analytic methods are nearly 10 times faster than the numerical methods for the isolated computation of the convolution, and around 4-5 times faster when used in an optimization routine to obtain parameter estimates. These results were obtained from five example data sets, one of which was examined in more detail to compare the estimates obtained using the different models, and with literature values.

Dynamic MRI for imaging tumor microvasculature: Comparison of susceptibility and relaxivity techniques in pelvic tumors

To assess the reproducibility of intrinsic relaxivity and both relaxivity‐ and susceptibility‐based dynamic contrast enhanced (DCE) MRI in pelvic tumors; to correlate kinetic parameters obtained and to assess whether acute antivascular effects are seen in response to cisplatin‐ or taxane‐based chemotherapy.

Primary Human Breast Adenocarcinoma: Imaging and Histologic Correlates of Intrinsic Susceptibility-weighted MR Imaging before and during Chemotherapy

PURPOSE To investigate the histopathologic and dynamic magnetic resonance (MR) imaging correlates of intrinsic susceptibility-weighted (ISW) MR imaging in patients with primary human breast adenocarcinoma and to assess the relationship between baseline transverse relaxation rate (R2*) and T2* relaxivity change (ΔR2*) and the response to neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS Institutional ethics approval and informed consent were obtained. Between September 2001 and January 2008, 83 women (median age, 46 years; age range, 26-72 years) with breast cancer were recruited to undergo dynamic contrast medium-enhanced (DCE), dynamic susceptibility contrast-enhanced (DSC), and ISW MR imaging before and after two cycles of NAC. After excluding necrotic, infiltrating, and invasive lobular carcinomas, 31 patients were available for baseline assessment and 27 were available for response assessment. Transfer constant, leakage space, rate constant, initial area under the gadolinium concentration-time curve at 60 seconds, relative blood volume (rBV), relative blood flow (rBF), and R2* were calculated. Relationships between baseline R2* and histopathologic variables (tumor grade, estrogen receptor status, progesterone receptor status, human epidermal growth factor 2 status), tumor size, and dynamic MR imaging parameters were sought. Baseline adenocarcinoma R2* (n = 31) and ΔR2* (n = 27) were correlated with final pathologic response. RESULTS Inverse correlations between baseline R2* and rBV (ρ = -0.48, P = .013) and rBF (ρ = -0.44, P = .024) were found, but not after NAC. No relationships were observed between baseline R2* and other kinetic imaging parameters, histopathologic characteristics, or tumor size (P > .05). Baseline R2* values were lower in tumors than in normal breast tissue (31.8 sec(-1) vs 36.2 sec(-1), P = .017) but not after NAC. Increases in R2* were observed after treatment (31.1 sec(-1) vs 34.8 sec(-1), P = .006), with larger increases correlating with pathologic response. ΔR2* was not as effective as DCE or DSC MR imaging parameters in the prediction of response. CONCLUSION R2* is influenced by blood volume in untreated breast adenocarcinomas. Increases in R2* after two cycles of NAC correlate with pathologic response. Therapy-induced uncoupling of the relationship between R2* and rBV and rBF is consistent with responding tumors becoming hypoxic early during treatment. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100421/-/DC1.

Carbogen breathing increases prostate cancer oxygenation: a translational MRI study in murine xenografts and humans

Hypoxia has been associated with poor local tumour control and relapse in many cancer sites, including carcinoma of the prostate. This translational study tests whether breathing carbogen gas improves the oxygenation of human prostate carcinoma xenografts in mice and in human patients with prostate cancer. A total of 23 DU145 tumour-bearing mice, 17 PC3 tumour-bearing mice and 17 human patients with prostate cancer were investigated. Intrinsic susceptibility-weighted MRI was performed before and during a period of carbogen gas breathing. Quantitative R2* pixel maps were produced for each tumour and at each time point and changes in R2* induced by carbogen were determined. There was a mean reduction in R2* of 6.4% (P=0.003) for DU145 xenografts and 5.8% (P=0.007) for PC3 xenografts. In all, 14 human subjects were evaluable; 64% had reductions in tumour R2* during carbogen inhalation with a mean reduction of 21.6% (P=0.0005). Decreases in prostate tumour R2* in both animal models and human patients as a result of carbogen inhalation suggests the presence of significant hypoxia. The finding that carbogen gas breathing improves prostate tumour oxygenation provides a rationale for testing the radiosensitising effects of combining carbogen gas breathing with radiotherapy in prostate cancer patients.

Comparison of free-breathing with navigator-controlled acquisition regimes in abdominal diffusion-weighted magnetic resonance images: Effect on ADC and IVIM statistics.

To evaluate the effect on diffusion‐weighted image‐derived parameters in the apparent diffusion coefficient (ADC) and intra‐voxel incoherent motion (IVIM) models from choice of either free‐breathing or navigator‐controlled acquisition.

Antivascular effects of neoadjuvant androgen deprivation for prostate cancer: an in vivo human study using susceptibility and relaxivity dynamic MRI.

PURPOSE The antivascular effects of androgen deprivation have been investigated in animal models; however, there has been minimal investigation in human prostate cancer. This study tested the hypothesis that androgen deprivation causes significant reductions in human prostate tumor blood flow and the induction of hypoxia at a magnitude and in a time scale relevant to the neoadjuvant setting before radiotherapy. METHODS AND MATERIALS Twenty patients were examined, each with five multi-parameter magnetic resonance imaging scans: two scans before the commencement of androgen suppression, one scan after 1 month of hormone treatment, and two further scans after 3 months of therapy. Quantitative parametric maps of the prostate informing on relative blood flow (rBF), relative blood volume (rBV), vascular permeability (transfer constant [K(trans)]), leakage space (v(e)) and blood oxygenation (intrinsic relaxivity [R(2)∗]) were calculated. RESULTS Tumor blood volume and blood flow decreased by 83% and 79%, respectively, in the first month (p < 0.0001), with 74% of patients showing significant changes. The proportion of individual patients who achieved significant changes in T1 kinetic parameter values after 3 months of androgen deprivation for tumor measurements was 68% for K(trans) and 53% for v(e) By 3 months, significant increases in R(2)∗ had occurred in prostate tumor, with a rise of 41.1% (p < 0.0001). CONCLUSIONS Androgen deprivation induces profound vascular collapse within 1 month of starting treatment. Increased R(2)∗ in regions of prostate cancer and a decrease in blood volume suggest a reduction in tumor oxygenation.

Reproducibility and correlation between quantitative and semiquantitative dynamic and intrinsic susceptibility‐weighted MRI parameters in the benign and malignant human prostate

To assess the reproducibility of relaxivity‐ and susceptibility‐based dynamic contrast‐enhanced magnetic resonance imaging (MRI) in the benign and malignant prostate gland and to correlate the kinetic parameters obtained.

Neuroendocrine Tumor Liver Metastases: Use of Dynamic Contrast-enhanced MR Imaging to Monitor and Predict Radiolabeled Octreotide Therapy Response

PURPOSE To evaluate dynamic contrast-enhanced (DCE) magnetic resonance (MR) imaging for monitoring and assessing treatment response in patients with neuroendocrine liver metastases treated using yttrium 90 ((90)Y)-labeled octreotide ((90)Y-DOTATOC). MATERIALS AND METHODS The study was approved by the local research and ethics committee and patient informed consent was obtained. Twenty patients with liver metastases from neuroendocrine tumors underwent T1-weighted DCE MR imaging of the liver before and at 2 months after intravenous (90)Y-DOTATOC treatment. Regions of interest were drawn around target lesions, as well as along liver outlines for each patient. A dual-input single-compartment model was used to compute parameters including fractional distribution volume and the arterial flow fraction. Pre- and posttreatment values were compared using Wilcoxon signed rank test. Treatment response was defined as showing a greater than 50% reduction in the nadir chromogranin A level within the 1st year after treatment. Pretreatment values of responders and nonresponders were compared using the Mann-Whitney test. A two-tailed P value of .008 or less, which accounts for multiple testing, was considered to indicate a significant difference. RESULTS In responders, tumor and whole liver distribution volume significantly increased after treatment (median tumor distribution volume, 0.182 vs 0.244; median whole liver distribution volume, 0.175 vs 0.207; P = .008). The pretreatment whole liver distribution volume was significantly lower in responders (median, 0.175 vs 0.248; P = .003), while pretreatment tumor arterial flow fraction was significantly higher in responders (median, 1.000 vs 0.7 ± 1, P = .006). CONCLUSION DCE MR imaging may be used to monitor the effects of peptide receptor radiolabeled targeted therapy in patients with neuroendocrine tumors liver metastases; a lower pretreatment distribution volume and high arterial flow fraction was associated with a better response to treatment.

Effects of platinum/taxane based chemotherapy on acute perfusion in human pelvic tumours measured by dynamic MRI

Dynamic contrast enhanced MRI (DCE-MRI) is being used increasingly in clinical trials to demonstrate that vascular disruptive and antiangiogenic agents target tumour microcirculation. Significant reductions in DCE-MRI kinetic parameters are seen within 4–24 and 48 h of treatment with vascular disruptive and antiangiogenic agents, respectively. It is important to know whether cytotoxic agents also cause significant acute reductions in these parameters, for reliable interpretation of results. This study investigated changes in transfer constant (Ktrans) and the initial area under the gadolinium curve (IAUGC) following the first dose of chemotherapy in patients with mostly gynaecological tumours. A reproducibility analysis on 20 patients (using two scans performed on consecutive days) was used to determine the significance of DCE-MRI parameter changes 24 h after chemotherapy in 18 patients. In 11 patients who received platinum alone or with a taxane, there were no significant changes in Ktrans or IAUGC in either group or individual patient analyses. When the remaining seven patients (treated with a variety of agents including platinum and taxanes) were included (n=18), there were also no significant changes in Ktrans. Therefore, if combination therapy does show changes in DCE-MRI parameters then the effects can be attributed to antivascular therapy rather than chemotherapy.