Exploratory radiomic features from integrated 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging are associated with contemporaneous metastases in oesophageal/gastroesophageal cancer.

PURPOSE: The purpose of this study was to determine if 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) features are associated with contemporaneous metastases in patients with oesophageal/gastroesophageal cancer. METHODS: Following IRB approval and informed consent, patients underwent a staging PET/MRI following 18F-FDG injection (326 ± 28 MBq) and 156 ± 23 min uptake time. First-order histogram and second-order grey level co-occurrence matrix features were computed for PET standardized uptake value (SUV) and MRI T1-W, T2-W, diffusion weighted (DWI) and apparent diffusion coefficient (ADC) images for the whole tumour volume. K-means clustering assessed the correlation of feature-pairs with metastases. Multivariate analysis of variance (MANOVA) was performed to assess the statistical separability of the groups identified by feature-pairs. Sensitivity (SN), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), and accuracy (ACC) were calculated for these features and compared with SUVmax, ADCmean and maximum diameter alone for predicting contemporaneous metastases. RESULTS: Twenty patients (18 males, 2 female; median 67 years, range 52-86) comprised the final study cohort; ten patients had metastases. Lower second-order SUV entropy combined with higher second-order ADC entropy were the best feature-pair for discriminating metastatic patients, MANOVA p value <0.001 (SN = 80%, SP = 80%, PPV = 80%, NPV = 80%, ACC = 80%). SUVmax (SN = 30%, SP = 80%, PPV = 60%, NPV = 53%, ACC = 55%), ADCmean (SN = 20%, SP = 70%, PPV = 40%, NPV = 47%, ACC = 45%) and tumour maximum diameter (SN = 10%, SP = 90%, PPV = 50%, NPV = 50%, ACC = 50%) had poorer sensitivity and accuracy. CONCLUSION: High ADC entropy combined with low SUV entropy is associated with a higher prevalence of metastases and a promising initial signature for future study.

Primary Rectal Cancer: Repeatability of Global and Local-Regional MR Imaging Texture Features.

Purpose To assess the day-to-day repeatability of global and local-regional magnetic resonance (MR) imaging texture features derived from primary rectal cancer. Materials and Methods After ethical approval and patient informed consent were obtained, two pretreatment T2-weighted axial MR imaging studies performed prospectively with the same imaging unit on 2 consecutive days in 14 patients with rectal cancer (11 men [mean age, 61.7 years], three women [mean age, 70.0 years]) were analyzed to extract (a) global first-order statistical histogram and model-based fractal features reflecting the whole-tumor voxel intensity histogram distribution and repeating patterns, respectively, without spatial information and (b) local-regional second-order and high-order statistical texture features reflecting the intensity and spatial interrelationships between adjacent in-plane or multiplanar voxels or regions, respectively. Repeatability was assessed for 46 texture features, and mean difference, 95% limits of agreement, within-subject coefficient of variation (wCV), and repeatability coefficient (r) were recorded. Results Repeatability was better for global parameters than for most local-regional parameters. In particular, histogram mean, median, and entropy, fractal dimension mean and standard deviation, and second-order entropy, homogeneity, difference entropy, and inverse difference moment demonstrated good repeatability, with narrow limits of agreement and wCVs of 10% or lower. Repeatability was poorest for the following high-order gray-level run-length (GLRL) gray-level zone size matrix (GLZSM) and neighborhood gray-tone difference matrix (NGTDM) parameters: GLRL intensity variability, GLZSM short-zone emphasis, GLZSM intensity nonuniformity, GLZSM intensity variability, GLZSM size zone variability, and NGTDM complexity, demonstrating wider agreement limits and wCVs of 50% or greater. Conclusion MR imaging repeatability is better for global texture parameters than for local-regional texture parameters, indicating that global texture parameters should be sufficiently robust for clinical practice. Online supplemental material is available for this article.

Positron Emission Tomography/Magnetic Resonance Imaging of Gastrointestinal Cancers.

As an integrated system, hybrid positron emission tomography/magnetic resonance imaging (PET/MRI) is able to provide simultaneously complementary high-resolution anatomic, molecular, and functional information, allowing comprehensive cancer phenotyping in a single imaging examination. In addition to an improved patient experience by combining 2 separate imaging examinations and streamlining the patient pathway, the superior soft tissue contrast resolution of MRI and the ability to acquire multiparametric MRI data is advantageous over computed tomography. For gastrointestinal cancers, this would improve tumor staging, assessment of neoadjuvant response, and of the likelihood of a complete (R0) resection in comparison with positron emission tomography or computed tomography.

Phase I trial of combretastatin A4 phosphate (CA4P) in combination with bevacizumab in patients with advanced cancer.

PURPOSE: The vascular disrupting agent (VDA) combretastatin A4 phosphate (CA4P) induces significant tumor necrosis as a single agent. Preclinical models have shown that the addition of an anti-VEGF antibody to a VDA attenuates the revascularization of the surviving tumor rim and thus significantly increases antitumor activity. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies received CA4P at 45, 54, or 63 mg/m(2) on day 1, day 8, and then every 14 days. Bevacizumab 10 mg/kg was given on day 8 and at subsequent cycles four hours after CA4P. Functional imaging with dynamic contrast enhanced-MRI (DCE-MRI) was conducted at baseline, after CA4P alone, and after cycle 1 CA4P + bevacizumab. RESULTS: A total of 63 mg/m(2) CA4P + 10 mg/kg bevacizumab q14 is the recommended phase II dose. A total of 15 patients were enrolled. Dose-limiting toxicities were grade III asymptomatic atrial fibrillation and grade IV liver hemorrhage in a patient with a history of hemorrhage. Most common toxicities were hypertension, headache, lymphopenia, pruritus, and pyrexia. Asymptomatic electrocardiographic changes were seen in five patients. Nine of 14 patients experienced disease stabilization. A patient with ovarian cancer had a CA125 response lasting for more than a year. DCE-MRI showed statistically significant reductions in tumor perfusion/vascular permeability, which reversed after CA4P alone but which were sustained following bevacizumab. Circulating CD34(+) and CD133(+) bone marrow progenitors increased following CA4P as did VEGF and granulocyte colony-stimulating factor levels. CONCLUSIONS: CA4P in combination with bevacizumab appears safe and well tolerated in this dosing schedule. CA4P induced profound vascular changes, which were maintained by the presence of bevacizumab.

Predicting response to neoadjuvant chemotherapy in primary breast cancer using volumetric helical perfusion computed tomography: a preliminary study.

OBJECTIVES: To investigate whether CT-derived vascular parameters in primary breast cancer predict complete pathological response (pCR) to neoadjuvant chemotherapy (NAC). METHODS: Twenty prospective patients with primary breast cancer due for NAC underwent volumetric helical perfusion CT to derive whole tumour regional blood flow (BF), blood volume (BV) and flow extraction product (FE) by deconvolution analysis. A pCR was achieved if no residual invasive cancer was detectable on pathological examination. Relationships between baseline BF, BV, FE, tumour size and volume, and pCR were examined using the Mann-Whitney U test. Receiver operating characteristic (ROC) curve analysis was performed to assess the parameter best able to predict response. Intra- and inter-observer variability was assessed using Bland-Altman statistics. RESULTS: Seventeen out of 20 patients completed NAC with four achieving a pCR. Baseline BF and FE were higher in patients who achieved a pCR compared with those who did not (P = 0.032); tumour size and volume were not significantly different (P > 0.05). ROC analysis revealed that BF and FE were able to identify responders effectively (AUC = 0.87; P = 0.03). There was good intra- and inter-observer agreement. CONCLUSIONS: Primary breast cancers which exhibited higher levels of perfusion before treatment were more likely to achieve a pCR to NAC.

Reproducibility of 2D and 3D fractal analysis techniques for the assessment of spatial heterogeneity of regional blood flow in rectal cancer.

PURPOSE: To characterize the two-dimensional (2D) and three-dimensional (3D) fractal properties of rectal cancer regional blood flow assessed by using volumetric helical perfusion computed tomography (CT) and to determine its reproducibility. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Ten prospective patients (eight men, two women; mean age, 72.3 years) with rectal adenocarcinoma underwent two repeated volumetric helical perfusion CT studies (four-dimensional adaptive spiral mode, 11.4-cm z-axis coverage) without intervening treatment within 24 hours, with regional blood flow derived by using deconvolution analysis. Two-dimensional and 3D fractal analyses of the rectal tumor were performed, after segmentation from surrounding structures by using thresholding, to derive fractal dimension and fractal abundance. Reproducibility was quantitatively assessed by using Bland-Altman statistics. Two-dimensional and 3D lacunarity plots were also generated, allowing qualitative assessment of reproducibility. Statistical significance was at 5%. RESULTS: Mean blood flow was 63.50 mL/min/100 mL ± 8.95 (standard deviation). Good agreement was noted between the repeated studies for fractal dimension; mean difference was -0.024 (95% limits of agreement: -0.212, 0.372) for 2D fractal analysis and -0.024 (95% limits of agreement: -0.307, 0.355) for 3D fractal analysis. Mean difference for fractal abundance was -0.355 (95% limits of agreement: -0.869, 1.579) for 2D fractal analysis and -0.043 (95% limits of agreement: -1.154, 1.239) for 3D fractal analysis. The 95% limits of agreement were narrower for 3D than 2D analysis. Lacunarity plots also visually confirmed close agreement between repeat studies. CONCLUSION: Regional blood flow in rectal cancer exhibits fractal properties. Good reproducibility was achieved between repeated studies with 2D and 3D fractal analysis.

Diffusion tensor imaging of the anal canal at 3 tesla: feasibility and reproducibility of anisotropy measures.

PURPOSE: To assess the feasibility and reproducibility of 3-tesla diffusion tensor imaging (DTI) of the anal canal. MATERIALS AND METHODS: DTI was performed in 25 men with no clinical history of anal canal disease undergoing MRI for prostate cancer. Analysis of fractional anisotropy (FA), relative anisotropy (RA), and apparent diffusion coefficient (ADC) were determined for the epithelial/subepithelial layer, internal sphincter, external sphincter, and puborectalis. The directionality of diffusion was recorded from color-coded tractography maps. Obturator internus and gluteus maximus served as reference muscles. Mean (SD) of values for FA, RA, and ADC were compared using analysis of variance. Intra and inter-rater agreement and test reproducibility (n = 5) was assessed by Bland-Altman statistics. RESULTS: Mean (SD) for the epithelial/subepithelial layer, internal, external sphincter, and puborectalis were as follows: FA: 0.283 (0.099); 0.337 (0.049); 0.415 (0.072); and 0.407 (0.062), respectively. RA: 0.241 (0.094); 0.292 (0.050); 0.371 (0.083); 0.361 (0.067), respectively; and ADC: 1.49 (0.23); 1.59 (0.19); 1.51 (0.28); and 1.54 (0.29) × 10(-3) mm(2) /s, respectively. Good overall intra and inter-rater agreement and test-retest reproducibility was noted (coefficient of variation of 4.8-19.4% and 5.9-12.9%, respectively). CONCLUSION: Anisotropy is evident in the anal canal with good inter-rater agreement and test reproducibility.

Diffusion tensor imaging (DTI) of desmoid tumours in familial adenomatous polyposis: initial experience.

PURPOSE: To assess the feasibility of diffusion tensor imaging (DTI) of desmoid tumours in familial adenomatous polyposis (FAP). MATERIALS AND METHODS: Following ethical approval and informed consent, FAP patients with desmoids underwent DTI. Fractional anisotropy (FA), relative anisotropy (RA) and apparent diffusion coefficient (ADC) were compared to control muscle using Mann-Whitney test; and to tumour site and signal intensity using one way analysis of variance (ANOVA). Imaging was repeated after 1 year. RESULTS: 15 desmoids (6 intra-abdominal; 6 abdominal wall, 3 extra-abdominal; size range: 1.6-22.9 cm) were evaluated in 9 patients. DTI was successful in 12/15 desmoid tumours. Median (range) of RA, FA and ADC were 0.23×10(-3) mm2/s (0.17-0.26); 0.27×10(-3) mm2/s (0.21-0.31); and 1.65×10(-3) mm2/s (1.39-1.91) for desmoids, significantly different from muscle: 0.27×10(-3) mm2/s (0.23-0.40), 0.32×10(-3) mm2/s (0.28-0.46), and 1.45×10(-3) mm2/s (0.92-1.63) (p=0.0001, p=0.0001, p=0.0016, respectively). There was no difference in RA, FA or ADC between tumour sites, or signal intensity (p>0.05). One year later, 2 patients had died. Tumour increased in size in 1 patient (+61%). DTI quantification was possible in only 8/13 tumours. FA, RA and ADC were not significantly different from baseline (p=0.77, 0.71 and 0.34, respectively). CONCLUSIONS: Assessment of water diffusion has the potential to provide insight into tumour microstructure and is feasible in desmoids. Desmoid tumours demonstrate anisotropy but diffusion is less restricted and less directional than in muscle.

Use of dynamic contrast-enhanced MR imaging to predict survival in patients with primary breast cancer undergoing neoadjuvant chemotherapy.

PURPOSE: To investigate whether early changes in vascular parameters determined with dynamic contrast material-enhanced magnetic resonance (MR) imaging after two cycles of neoadjuvant chemotherapy (NAC) are predictive of disease-free and overall survival in primary breast cancer. MATERIALS AND METHODS: Institutional ethics approval and informed consent were obtained. Patients with primary breast cancer (median age, 45 years; age range, 22-70 years) recruited from January 2001 to September 2008 underwent dynamic contrast-enhanced MR imaging before and after two cycles of NAC. Quantitative and semiquantitative kinetic parameters were calculated, including the volume transfer constant (K(trans)) and the initial area under the gadolinium concentration-time curve over 60 seconds (IAUGC(60)). Cut points optimized to the receiver operating characteristic curve were used to dichotomize MR imaging data for Kaplan-Meier survival analysis. MR imaging parameters and known prognostic indicators in primary breast cancer were correlated with disease-free and overall survival by using the Cox proportional hazards model for univariate and multivariate analyses. RESULTS: MR imaging was performed before (n = 62) and after (n = 58) two cycles of NAC. The median follow-up time was 43.9 months for disease-free survival and 60.3 months for overall survival. There were 28 recurrences; 26 patients had distant metastases (two had additional local recurrence) and two had local recurrence only. There were 20 deaths, all of which were related to breast cancer. At univariate analysis, progesterone receptor status, the type of surgery performed, higher posttreatment K(trans) (P = .048), and larger posttreatment IAUGC(60) (P = .035) were significant predictors of worse disease-free survival. At multivariate analysis, progesterone receptor status (P = .002) and mean transit time (P = .025) were significant predictors of disease-free survival. Univariate analysis showed that clinical tumor stage (P = .005), progesterone receptor status (P = .025), and type of surgery performed (P = .017) were significant predictors of overall survival. Higher posttreatment K(trans) (P = .043), larger IAUGC(60) (P = .029), and larger tumor size at posttreatment MR imaging were predictive of worse overall survival (P = .018). Of these variables, K(trans) remained an independent indicator of overall survival (P = .038). CONCLUSION: Higher posttreatment tumor vascularization as depicted with dynamic contrast-enhanced MR imaging may be associated with higher recurrence and lower survival rates. Dynamic contrast-enhanced MR imaging parameters, in conjunction with traditional prognostic factors, have the potential to be prognostic biomarkers for disease-free and overall survival in primary breast cancer.

Vascular characterisation of triple negative breast carcinomas using dynamic MRI.

OBJECTIVES: Triple-negative (ER-/PR-/HER2-) breast carcinomas (TNBC) are aggressive tumours with underexplored imaging features. This study investigates whether their vascular characteristics as assessed by dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast-enhanced (DSC) MRI are distinct from the prognostically more favourable ER+/PR+/HER2- cancers. METHODS: Patients with primary breast cancer underwent MRI before neoadjuvant chemotherapy and were identified as ER-/PR-/HER2- or ER+/PR+/HER2- from core biopsy specimens. MRI parameters reflecting tissue perfusion, permeability, and extracellular leakage space were measured. Values for inflow transfer constant (K(trans)), outflow rate constant (k(ep)), leakage space (v(e)), area under the gadolinium curve (IAUGC(60) ), relative blood volume (rBV) and flow (rBF), and Mean Transit Time (MTT) were compared across receptor status and with known prognostic variables. RESULTS: Thirty seven patients were assessable in total (16 ER-/PR-/HER2-, 21 ER+/PR+/HER2-). Lower v(e) (p = 0.001), shorter MTT (p = 0.007) and higher k(ep) values (p = 0.044) were observed in TNBC. v(e) was lower across all T stages, node-negative (p = 0.004) and low-grade TNBC (p = 0.037). v(e) was the best predictor of triple negativity (ROC AUC 0.80). CONCLUSIONS: TNBC possess characteristic features on imaging, with lower extracellular space (higher cell density) and higher contrast agent wash-out rate (higher vascular permeability) suggesting a distinctive phenotype detectable by MRI.

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.

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.

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

PURPOSE: 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. MATERIALS AND METHODS: Twenty patients with prostate cancer underwent paired scans before and after androgen deprivation therapy. Quantitative parametric maps for T(1)- and T(2)*-weighted parameters were calculated (K(trans), k(ep),v(e), IAUC(60), rBV, rBF, and R(2)*). The reproducibility of and correlation between each parameter were determined using standard methods at both timepoints. RESULTS: T(1)-derived parameters are more reproducible than T(2)*-weighted measures, both becoming more variable following androgen deprivation (variance coefficients for prostate K(trans) and rBF increased from 13.9%-15.8% and 42.5%-90.8%, respectively). Tumor R(2)* reproducibility improved after androgen ablation (23.3%-11.8%). IAUC(60) correlated strongly with K(trans), v(e), and k(ep) (all P < 0.001). R(2)* did not correlate with other parameters. CONCLUSION: This study is the first to document the variability and repeatability of T(1)- and T(2)*-weighted dynamic MRI and intrinsic susceptibility-weighted MRI for the various regions of the human prostate gland before and after androgen deprivation. These data provide a valuable source of reference for groups that plan to use dynamic contrast-enhanced MRI or intrinsic susceptibility-weighted MRI for the assessment of treatment response in the benign or malignant prostate.

A phase I trial of radioimmunotherapy with 131I-A5B7 anti-CEA antibody in combination with combretastatin-A4-phosphate in advanced gastrointestinal carcinomas.

PURPOSE: In preclinical models, radioimmunotherapy with (131)I-A5B7 anti-carcinoembryonic antigen (CEA) antibody ((131)I-A5B7) combined with the vascular disruptive agent combretastatin-A4-phosphate (CA4P) produced cures unlike either agent alone. We conducted a phase I trial determining the dose-limiting toxicity (DLT), maximum tolerated dose, efficacy, and mechanism of this combination in patients with gastrointestinal adenocarcinomas. EXPERIMENTAL DESIGN: Patients had CEA of 10 to 1,000 microg/L, QTc < or =450 ms, no cardiac arrhythmia/ischaemia, and adequate hematology/biochemistry. Tumor was suitable for blood flow analysis by dynamic contrast enhanced-magnetic resonance imaging (MRI). The starting dose was 1,800 MBq/m(2) of (131)I-A5B7 on day 1 and 45 mg/m(2) CA4P given 48 and 72 hours post-(131)I-A5B7, then weekly for up to seven weeks. RESULTS: Twelve patients were treated, with mean age of 63 years (range, 32-77). Two of six patients at the first dose level had DLTs (grade 4 neutropenia). The dose was reduced to 1,600 MBq/m(2), and CA4P escalated to 54 mg/m(2). Again, two of six patients had DLTs (neutropenia). Of ten assessable patients, three had stable disease and seven had progressive disease. Single-photon emission computed tomography confirmed tumor antibody uptake in all 10 patients. DCE-MRI confirmed falls in kinetic parameters (K(trans)/IAUGC(60)) in 9 of 12 patients. The change of both pharmacokinetic parameters reached a level expected to produce efficacy in one patient who had a minor response on computed tomography and a reduced serum tumor marker level. CONCLUSIONS: This is believed to be the first trial reporting the combination of radioimmunotherapy and vascular disruptive agent; each component was shown to function, and myelosuppression was dose-limiting. Optimal dose and timing of CA4P, and moderate improvements in the performance of radioimmunotherapy seem necessary for efficacy.

Reproducibility and changes in the apparent diffusion coefficients of solid tumours treated with combretastatin A4 phosphate and bevacizumab in a two-centre phase I clinical trial.

The purpose was to determine the reproducibility of apparent diffusion coefficient (ADC) measurements in a two-centre phase I clinical trial; and to track ADC changes in response to the sequential administration of the vascular disrupting agent, combretastatin A4 phosphate (CA4P), and the anti-angiogenic drug, bevacizumab. Sixteen patients with solid tumours received CA4P and bevacizumab treatment. Echo-planar diffusion-weighted MRI was performed using six b values (b = 0-750 s/mm(2)) before (x2), and at 3 and 72 h after a first dose of CA4P. Bevacizumab was given 4 h after a second dose of CA4P, and imaging performed 3 h post CA4P and 72 h after bevacizumab treatment. The coefficient of repeatability (r) of ADC total (all b values), ADC high (b = 100-750) and ADC low (b = 0-100) was calculated by Bland-Altman analysis. The ADC total and ADC high showed good measurement reproducibility (r% = 13.3, 14.1). There was poor reproducibility of the perfusion-sensitive ADC low (r% = 62.5). Significant increases in the median ADC total and ADC high occurred at 3 h after the second dose of CA4P (p < 0.05). ADC measurements were highly reproducible in a two-centre clinical trial setting and appear promising for evaluating the effects of drugs that target tumour vasculature.

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 (K(trans), k(ep), v(e), 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 K(trans), k(ep), MaxGd, rBV, and rBF were significantly correlated with both final clinical and pathologic response (P < 0.01). Change in K(trans) 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.

Hypoxia in prostate cancer: correlation of BOLD-MRI with pimonidazole immunohistochemistry-initial observations.

PURPOSE: To investigate the ability of blood oxygen level-dependent (BOLD) MRI to depict clinically significant prostate tumor hypoxia. METHODS AND MATERIALS: Thirty-three patients with prostate carcinoma undergoing radical prostatectomy were studied preoperatively, using gradient echo sequences without and with contrast medium enhancement, to map relative tissue oxygenation according to relaxivity rates and relative blood volume (rBV). Pimonidazole was administered preoperatively, and whole-mount sections of selected tumor-bearing slices were stained for pimonidazole fixation and tumor and nontumor localization. Histologic and imaging parameters were independently mapped onto patient prostate outlines. Using 5-mm grids, 861 nontumor grid locations were compared with 237 tumor grids (with >50% tumor per location) using contingency table analysis with respect to the ability of imaging to predict pimonidazole staining. RESULTS: Twenty patients completed the imaging and histologic protocols. Pimonidazole staining was found in 33% of nontumor and in 70% of tumor grids. The sensitivity of the MR relaxivity parameter R(2)* in depicting tumor hypoxia was high (88%), improving with the addition of low rBV information (95%) without changing specificity (36% and 29%, respectively). High R(2)* increased the positive predictive value for hypoxia by 6% (70% to 76%); conversely, low R(2)* decreased the likelihood of hypoxia being present by 26% (70% to 44%) and by 41% (71% to 30%) when combined with rBV information. CONCLUSION: R(2)* maps from BOLD-MRI have high sensitivity but low specificity for defining intraprostatic tumor hypoxia. This together with the negative predictive value of 70% when combined with blood volume information makes BOLD-MRI a potential noninvasive technique for mapping prostatic tumor hypoxia.

Inter- and intraobserver variability in the evaluation of dynamic breast cancer MRI.

PURPOSE: To quantify variations within and between observers ascribable to manual region of interest (ROI) placement in patients with breast cancer undergoing dynamic MRI. MATERIALS AND METHODS: Expert and nonexpert observers independently outlined tumor ROIs on 30 dynamic T(1)-weighted (T(1)W) MRI scans on five occasions over two months. Lesion size (number of pixels) and kinetic parameter estimates, including the transfer constant (K(trans)), were calculated for each ROI placement. Inter- and intraobserver variability was assessed with respect to the interval between drawings, lesion morphology, and observer experience. RESULTS: For the nonexpert, the variability reduced with decreasing time intervals between ROI drawings (the coefficient of variance (wCV) values at two months, two weeks, one day, and same-day time intervals were respectively 11.6%, 10.7%, 4.8%, and 2.6% for lesion size, and 8.9%, 9.7%, 6.7%, and 3.2% for K(trans)). For the expert observer, the variability was smaller overall and more constant, but improved for same-day ROI placements (region size wCV: 7.5%, 6.2%, 7.1%, and 3.7%; K(trans) wCV: 5.4%, 5.3%, 5.6%, and 4.5%). CONCLUSION: Significant observer variability in manual ROI placement occurs in dynamic MRI of breast cancer. For serial patient studies, ROI placements should be outlined at the same sitting to minimize observer error.

Combretastatin A4 phosphate has tumor antivascular activity in rat and man as demonstrated by dynamic magnetic resonance imaging.

PURPOSE: Combretastatin A4 phosphate (CA4P) is a novel vascular targeting agent. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) studies were performed to examine changes in parameters related to blood flow and vascular permeability in tumor and normal tissue after CA4P treatment. MATERIALS AND METHODS: Changes in kinetic DCE-MRI parameters (transfer constant [Ktrans] and area under contrast medium-time curve [AUC]) over 24 hours after treatment with CA4P were measured in 18 patients in a phase I trial and compared with those obtained in the rat P22 carcinosarcoma model, using the same imaging technique. Rats were treated with 30 mg/kg of CA4P; patients received escalating doses from 5 to 114 mg/m2. RESULTS: A similar pattern and time course of change in tumor and normal tissue parameters was seen in rats and humans. Rat tumor Ktrans was reduced by 64% 6 hours after treatment with CA4P (30 mg/kg). No significant reductions in kidney or muscle parameters were seen. Significant reductions were seen in tumor Ktrans in six of 16 patients treated at >or= 52 mg/m2, with a significant group mean reduction of 37% and 29% at 4 and 24 hours, respectively, after treatment. The mean reduction in tumor initial area under the gadolinium-diethylenetriamine pentaacetic acid concentration-time curve (AUC) was 33% and 18%, respectively, at these times. No reduction was seen in muscle Ktrans or in kidney AUC in group analysis of the clinical data. CONCLUSION: CA4P acutely reduces Ktrans in human as well as rat tumors at well-tolerated doses, with no significant changes in kidney or muscle, providing proof of principle that this drug has tumor antivascular activity in rats and humans.

Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging.

PURPOSE: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) causes vascular shutdown in preclinical models. Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) studies were performed in the phase I trials to examine changes related to blood flow and permeability in tumor and muscle. PATIENTS AND METHODS: Sixteen patients treated with DMXAA from 500 to 4,900 mg/m(2) had DCE-MRI examinations before and after treatment. The maximum gradient, the maximum enhancement, and the area under the signal-intensity-time curve (AUC) over the first 90 seconds were calculated for each pixel in regions of interest (ROIs) in muscle and tumor, and the median value for each ROI was obtained. Changes after treatment were compared with 95% limits of agreement for an individual and for groups using data from our reproducibility study. RESULTS: Nine of 16 patients had significant reductions in AUC 24 hours after the first dose of DMXAA, and eight of 11 patients had reductions of up to 66% in AUC 24 hours after the last dose. Mean reductions in gradient, enhancement, and AUC were 25%, 18%, and 31%, respectively, 24 hours after the last dose, significantly greater than the 95% limits of change for a group of 11 patients. Enhancement and AUC in muscle 24 hours after the first dose were significantly reduced, but no significant changes were seen 24 hours after the last dose. CONCLUSION: DMXAA significantly reduces DCE-MRI parameters related to tumor blood flow, over a wide dose range, consistent with the reported tumor vascular targeting activity. Further clinical evaluation of DMXAA is warranted.