Radiofrequency ablation with four electrodes as a building block for matrix radiofrequency ablation: Ex vivo liver experiments and finite element method modelling. Influence of electric and activation mode on coagulation size and geometry.

PURPOSE: Radiofrequency ablation (RFA) is increasingly being used to treat unresectable liver tumors. Complete ablation of the tumor and a safety margin is necessary to prevent local recurrence. With current electrodes, size and shape of the ablation zone are highly variable leading to unsatisfactory local recurrence rates, especially for tumors >3 cm. In order to improve predictability, we recently developed a system with four simple electrodes with complete ablation in between the electrodes. This rather small but reliable ablation zone is considered as a building block for matrix radiofrequency ablation (MRFA). In the current study we explored the influence of the electric mode (monopolar or bipolar) and the activation mode (consecutive, simultaneous or switching) on the size and geometry of the ablation zone. MATERIALS AND METHODS: The four electrode system was applied in ex vivo bovine liver. The electric and the activation mode were changed one by one, using constant power of 50 W in all experiments. Size and geometry of the ablation zone were measured. Finite element method (FEM) modelling of the experiment was performed. RESULTS: In ex vivo liver, a complete and predictable coagulation zone of a 3 × 2 × 2 cm block was obtained most efficiently in the bipolar simultaneous mode due to the combination of the higher heating efficacy of the bipolar mode and the lower impedance by the simultaneous activation of four electrodes, as supported by the FEM simulation. CONCLUSIONS: In ex vivo liver, the four electrode system used in a bipolar simultaneous mode offers the best perspectives as building block for MRFA. These results should be confirmed by in vivo experiments.

Prognostic features of breast cancer differ between women in the Democratic Republic of Congo and Belgium.

OBJECTIVES: Compared to European women, breast cancers in African women present at a younger age, with a higher tumor grade and are more often estrogen receptor (ER)/progesterone receptor (PR) negative. We here investigate the histopathological and immunohistochemical characteristics (ER, PR and human epidermal growth receptor 2 (HER2)) and the proportion of triple negative (Tneg) invasive breast cancers from an unselected series of patients diagnosed in Kinshasa, and compare them to a population of Caucasian women with a palpable breast cancer. MATERIALS AND METHODS: From 2010 till 2013, during the first breast cancer awareness campaign, organized in Kinshasa, 87 patients were diagnosed with invasive breast cancer. Diagnose was based on core biopsy. The control group consisted of Caucasian women (University Hospitals of Leuven, Belgium) with a palpable mass, diagnosed between 2000 till 2009, treated with surgery of which the histopathological and immunohistochemical characteristics were collected on excision specimens. Each patient in the Kinshasa group was matched based on age and tumor size to one or more patients of the Leuven database. Differences between both groups with respect to hormone receptors (ER, PR, HER2, Tneg) or grade are presented as relative risks (RR). The analysis is based on a log-binomial model accounting for clustering through matching by a random intercept for cluster. Differences between both groups with respect to hormone receptors correcting for grade is performed by the inclusion of grade as a covariate in the model. RESULTS: After adjusting for age, tumor volume and tumor grade, ER was more frequently negative (RR = 0.71, p < 0.001), with a trend in the same direction for PR (RR = 0.87, p = 0.057), and HER2 more often positive (RR = 1.60, p = 0.015) compared to the group from the University Hospitals of Leuven. There was no difference in the proportion of breast cancers being triple negative. Sub-analysis showed that the higher HER2 positive rate was only observed in older patients (≥50y: RR = 2.07, p = 0.007) whereas no difference in HER2 positive rate was found in younger patients (<50y: RR = 1.30, p = 0.358). A higher ER negative rate was observed in both age groups, however more pronounced in older patients (≥50y: RR = 0.64, p = 0.001; <50y: RR = 0.79, p = 0.018). CONCLUSION: Breast cancer in women of Kinshasa presents at younger age and is more aggressive (more frequently ER negative and HER2 positive) compared to Caucasian women and this is more pronounced in older women (>50y). Only the ER results were concordant with the results of two similar studies (comparing an African with a European group), but were different when compared to studies on African-American women with breast cancer. This information is very important considering the treatment option: as more tumors are ER negative, endocrine therapy cannot be given while chemotherapy is often too expensive.

Bipolar radiofrequency ablation with 2 × 2 electrodes as a building block for matrix radiofrequency ablation: Ex vivo liver experiments and finite element method modelling.

PURPOSE: Size and geometry of the ablation zone obtained by currently available radiofrequency (RF) electrodes is highly variable. Reliability might be improved by matrix radiofrequency ablation (MRFA), in which the whole tumour volume is contained within a cage of x × y parallel electrodes. The aim of this study was to optimise the smallest building block for matrix radiofrequency ablation: a recently developed bipolar 2 × 2 electrode system. MATERIALS AND METHODS: In ex vivo bovine liver, the parameters of the experimental set-up were changed one by one. In a second step, a finite element method (FEM) modelling of the experiment was performed to better understand the experimental findings. RESULTS: The optimal power to obtain complete ablation in the shortest time was 50-60 W. Performing an ablation until impedance rise was superior to ablation for a fixed duration. Increasing electrode diameter improved completeness of ablation due to lower temperature along the electrodes. A chessboard pattern of electrode polarity was inferior to a row pattern due to an electric field void in between the electrodes. Variability of ablation size was limited. The FEM correctly simulated and explained the findings in ex vivo liver. CONCLUSIONS: These experiments and FEM modelling allowed a better insight in the factors influencing the ablation zone in a bipolar 2 × 2 electrode RF system. With optimal parameters, complete ablation was obtained quickly and with limited variability. This knowledge will be useful to build a larger system with x × y electrodes for MRFA.

From the set-up of a screening program of breast cancer patients to the identification of the first BRCA mutation in the DR Congo.

BACKGROUND: Breast cancer incidence in African population is low compared to western countries but the mortality rate is higher and the disease presents at a younger age and at a more advanced stage. The World Health Organisation and the Breast Health Global Initiative concluded that in low and middle income countries early breast cancer detection can be achieved by informing women on symptoms of breast cancer, on the practice of breast self-examination and clinical breast examination by trained health care workers. Based on these recommendations, we set up a breast cancer awareness campaign in Kinshasa, Democratic Republic of Congo (DRC). This paper describes the strategy that was established and the results that were achieved. METHODS: A breast cancer awareness campaign was started in 2010 and data were collected until the end of 2012. Clinicians (expert group) trained nurses and health care workers (awareness groups) on clinical, technical and social aspects of breast cancer. Different channels were used to inform women about the campaign and clinical data (on medical and family history) were collected. The participating women were investigated with clinical breast examination by the awareness group. Women in whom a palpable mass was detected were referred to the hospital: they received a mammography and ultrasound and--in case of suspicious findings--additionally a core needle biopsy. In case of a positive family history, a blood sample was taken for genetic investigation. RESULTS: In total, 4,315 women participated, resulting in 1,113 radiological breast examinations, performed in the General Hospital of Kinshasa of which 101 turned out to be malignant lesions. Fifty six percent of the women with breast cancer were less than 50 years old and 75% (65/87) were stage III tumors. A BRCA gene mutation was identified in a family with a severe history of breast cancer. CONCLUSIONS: Even without financial support, it was possible to start an awareness campaign for breast cancer in Kinshasa. This campaign increased the awareness on cancer of the women in Kinshasa. The results demonstrate that this campaign had an immediate impact on patients and their families.

Separate calculation of DW-MRI in assessing therapeutic effect in liver tumors in rats.

AIM: To explore whether the antitumor effect of a vascular disrupting agent (VDA) would be enhanced by combining with an antiangiogenic agent, and whether such synergistic effects can be effectively evaluated with separate calculation of diffusion weighted magnetic resonance imaging (DW-MRI). METHODS: Thirty-seven rats with implanted liver tumors were randomized into the following three groups: (1) ZD6126, a kind of VDA; (2) ZDTHA, ZD6126 in combination with an antiangiogenic, thalidomide; and (3) control. Morphological DW-MRI were performed and quantified before, 4 h and 2 d after treatment. The apparent diffusion coefficient (ADC) values were calculated separately for low b values (ADC(low)), high b values (ADC(high)) and all b values (ADC(all)). The tissue perfusion contribution, ADC(perf), was calculated as ADC(low)-ADC(high). Imaging findings were finally verified by histopathology. RESULTS: The combination therapy with ZDTHA significantly delayed tumor growth due to synergistic effects by inducing cumulative tumor necrosis. In addition to delaying tumor growth, ZDTHA caused tumor necrosis in an additive manner, which was verified by HE staining. Although both ADC(high) and ADC(all) in the ZD6126 and ZDTHA groups were significantly higher compared to those in the control group on day 2, the entire tumor ADC(high) of ZDTHA was even higher than that of ZD6126, but the significant difference was not observed for ADC(all) between ZDTHA and ZD6126. This indicated that the perfusion insensitive ADC(high) values calculated from high b value images performed significantly better than ADC(all) for the monitoring of tumor necrosis on day 2. The perfusion sensitive ADC(perf) derived from ADC(low) by excluding high b value effects could better reflect the reduction of blood flow due to the vessel shutdown induced by ZD6126, compared to the ADC(low) at 4 h. The ADC(perf) could provide valuable perfusion information from DW-MRI data. CONCLUSION: The separate calculation of ADC is more useful than conventional averaged ADC in evaluating the efficacy of combination therapy with ZD6126 and thalidomide for solid tumors.

Bipolar radiofrequency ablation with four electrodes: ex vivo liver experiments and finite element method analysis. Influence of inter-electrode distance on coagulation size and geometry.

PURPOSE: The aim of this study was to develop an electrode system with simple needle electrodes which would allow a reliable and predictable ablation zone with radiofrequency ablation (RFA). MATERIALS AND METHODS: In the first step, four parallel electrodes (active length 3 cm, diameter 1.8 mm) were inserted in ex vivo bovine liver. A power of 50 W was applied between two pairs of electrodes for 10 min or until current shut-off due to impedance rise. In the second step, the influence of changing inter-electrode distance on coagulation size and geometry was measured. In the third step, a finite element method (FEM) analysis of the experiment was performed to better understand the experimental findings. RESULTS: A bipolar four-electrode system with templates adjusting the inter-electrode distance was successfully developed for ex vivo experiments. A complete and reliable coagulation zone of a 3 × 2 × 2-cm block was obtained most efficiently with an inter-electrode distance of 2 cm in 5.12 ± 0.71 min. Above 2 cm, coagulation was incomplete due to a too low electric field, as demonstrated by the FEM analysis. CONCLUSIONS: The optimal inter-electrode distance of the present bipolar four-electrode system was 2 cm, allowing a reliable and predictable ablation zone in ex vivo liver. The FEM analysis correctly simulated and explained the findings in ex vivo liver. The experimental set-up may serve as a platform to gain more insight and to optimise the application of RFA by means of four or more simple needle electrodes.

Enhanced antitumor efficacy of a vascular disrupting agent combined with an antiangiogenic in a rat liver tumor model evaluated by multiparametric MRI.

A key problem in solid tumor therapy is tumor regrowth from a residual viable rim after treatment with a vascular disrupting agent (VDA). As a potential solution, we studied a combined treatment of a VDA and antiangiogenic. This study was approved by the institutional ethical committee for the use and care of laboratory animals. Rats with implanted liver tumors were randomized into four treatment groups: 1) Zd6126 (Zd); 2) Thalidomide (Tha); 3) Zd in combination with Tha (ZdTha); and 4) controls. Multiparametric MRIs were performed and quantified before and after treatment. Circulating endothelial progenitor cells (EPCs) and plasma stromal cell-derived factor-1α (SDF-1α) were monitored. Tumor apoptosis, necrosis, and microvessels were verified by histopathology. A single use of Zd or Tha did not significantly delay tumor growth. The combined ZdTha showed enhanced antitumor efficacy due to synergistic effects; it induced a cumulative tumor apoptosis or necrosis, which resulted in significant delay in tumor growth and reduction in the viable tumor rim; it also reduced tumor vessel permeability; and it improved tumor hemodynamic indexes, most likely via a transient normalization of tumor vasculature induced by Tha. A stepwise linear regression analysis showed that the apparent diffusion coefficient was an independent predictor of tumor growth. We found no significant increases in Zd-induced circulating EPCs or plasma SDF-1α. ZdTha showed improved therapeutic efficacy in solid tumors compared to either agent alone. The therapeutic effects were successfully tracked in vivo with multiparametric MRI.

Comparison of two vascular-disrupting agents at a clinically relevant dose in rodent liver tumors with multiparametric magnetic resonance imaging biomarkers.

We sought to compare the therapeutic efficacy between two vascular-disrupting agents, combretastatin A4 phosphate (CA4P) and ZD6126, at a clinically relevant dose on tumor models with magnetic resonance imaging (MRI). Thirty rats with liver rhabdomyosarcoma were randomized into CA4P (10 mg/kg), ZD6126 (10 mg/kg), and control group (n=10 for each group). Multiparametric MRI biomarkers including tumor volume, enhancement ratio, necrosis ratio, apparent diffusion coefficient (ADC), and K (volume transfer constant) derived from T2-weighted, T1-weighted, contrast-enhanced T1-weighted, and diffusion-weighted imaging, and dynamic contrast-enhanced MRI were compared at pretreatment, 1 h, 6 h, 24 h, 48 h, and 120 h posttreatment; they were validated using ex-vivo techniques. Relative to rapidly growing tumors without necrosis in control rats, tumors grew slower in the CA4P group compared with the ZD6126 group with a higher necrosis ratio at 120 h (P<0.05), as proven by histopathology. In the CA4P group, K decreased from 1 h until 6 h, and partially recovered at 120 h. In the ZD6126 group, the reduced K at 1 h began to rebound from 6 h and exceeded the baseline value at 120 h (P<0.05), parallel to evolving enhancement ratios (P<0.05). ADC revealed more necrotic tumors with CA4P versus ZD6126 at 120 h (P<0.05). The different tumor responses were confirmed by ex-vivo microangiography and histopathology. CA4P was more effective than ZD6126 in impairing blood supply, inducing necrosis, and delaying growth in rat liver tumors at a clinically relevant dose. A single dose of vascular-disrupting agent was insufficient to destroy the tumor. The multiparametric MRI biomarkers enabled in-vivo noninvasive comparison of therapeutic efficacy between CA4P and ZD6126.

A dual-targeting anticancer approach: soil and seed principle.

PURPOSE: To test the hypothesis that targeting the microenvironment (soil) may effectively kill cancer cells (seeds) through a small-molecular weight sequential dual-targeting theragnostic strategy, or dual-targeting approach. MATERIALS AND METHODS: With approval from the institutional animal care and use committee, 24 rats were implanted with 48 liver rhabdomyosarcomas (R1). First, the vascular-disrupting agent combretastatin A4 phosphate (CA4P) was injected at a dose of 10 mg/kg to cause tumor necrosis, which became a secondary target. Then, the necrosis-avid agent hypericin was radiolabeled with iodine 131 to form (131)I-hypericin, which was injected at 300 MBq/kg 24 hours after injection of CA4P. Both molecules have small molecular weight, are naturally or synthetically derivable, are intravenously injectable, and are of unique targetablities. The tumor response in the dual-targeting group was compared with that in vehicle-control and single-targeting (CA4P or (131)I-hypericin) groups with in vivo magnetic resonance imaging and scintigrams and ex vivo gamma counting, autoradiography, and histologic analysis. Tumor volumes, tumor doubling time (TDT), and radiobiodistribution were analyzed with statistical software. P values below .05 were considered to indicate a significant difference. RESULTS: Eight days after treatment, the tumor volume of rhabdomyosarcoma in the vehicle-control group was double that in both single-targeting groups (P < .001) and was five times that in the dual-targeting group (P < .0001), without treatment-related animal death. The TDT was significantly longer in the dual-targeting group (P < .0001). Necrosis appeared as hot spots on scintigrams, corresponding to 3.13% of the injected dose of (131)I-hypericin per gram of tissue (interquartile range, 2.92%-3.97%) and a target-to-liver ratio of 20. The dose was estimated to be 100 times the cumulative dose of 50 Gy needed for radiotherapeutic response. Thus, accumulated (131)I-hypericin from CA4P-induced necrosis killed residual cancer cells with ionizing radiation and inhibited tumor regrowth. CONCLUSION: This dual-targeting approach may be a simple and workable solution for cancer treatment and deserves further exploitation.

Comparison between nonspecific and necrosis-avid gadolinium contrast agents in vascular disrupting agent-induced necrosis of rodent tumors at 3.0T.

OBJECTIVE: : To compare a commercial contrast agent (CA) Dotarem and a necrosis-avid CA (NACA) for their ability to evaluate the therapeutic necrosis with a vascular disrupting agent (VDA) on magnetic resonance imaging in rodent liver tumors to determine which could better correlate with the histopathologic outcome. METHODS: : After the VDA treatment, 16 rats with 32 liver rhabdomyosarcomas were randomized into Dotarem and NACA groups (n = 8 per group) for both interindividual and intraindividual comparisons. T2-weighted imaging, T1-weighted imaging (T1WI), contrast-enhanced T1-weighted imaging (CE-T1WI), and diffusion-weighted imaging were performed at baseline, after VDA treatment and CA injections. The enhancing efficacy of CAs at immediate and delayed enhancement on CE-T1WI in viable tumor and necrosis was compared. Tumor necrosis ratios calculated from NACA and Dotarem were compared and correlated with gold-standard histopathology. RESULTS: : On the immediate CE-T1WI, viable tumor was enhanced by either CA. On the delayed CE-T1WI at 30 minutes, both CAs failed to demarcate viable tumor from necrosis. At 24 hours post-NACA, the necrosis was clearly distinguished from viable tumor and thus derived necrosis ratio matched that from histopathology (P = 0.99); necrosis ratio from Dotarem was significantly lower than that from NACA and histopathology (P < 0.05, both), with a higher correlation of NACA than that of Dotarem with histopathology (r = 0.99 vs. r = 0.82). CONCLUSIONS: : NACA better evaluated VDA-induced tumor necrosis than nonspecific CA on T1WI in tumor models of rat liver. NACA showed a closer correlation with histopathology than nonspecific CA for the delineation of true necrosis. Delayed enhancement on T1WI with nonspecific CA is not suitable for the assessment of VDA-induced tumor necrosis.

Multiparametric MRI biomarkers for measuring vascular disrupting effect on cancer.

Solid malignancies have to develop their own blood supply for their aggressive growth and metastasis; a process known as tumor angiogenesis. Angiogenesis is largely involved in tumor survival, progression and spread, which are known to be significantly attributed to treatment failures. Over the past decades, efforts have been made to understand the difference between normal and tumor vessels. It has been demonstrated that tumor vasculature is structurally immature with chaotic and leaky phenotypes, which provides opportunities for developing novel anticancer strategies. Targeting tumor vasculature is not only a unique therapeutic intervention to starve neoplastic cells, but also enhances the efficacy of conventional cancer treatments. Vascular disrupting agents (VDAs) have been developed to disrupt the already existing neovasculature in actively growing tumors, cause catastrophic vascular shutdown within short time, and induce secondary tumor necrosis. VDAs are cytostatic; they can only inhibit tumor growth, but not eradicate the tumor. This novel drug mechanism has urged us to develop multiparametric imaging biomarkers to monitor early hemodynamic alterations, cellular dysfunctions and metabolic impairments before tumor dimensional changes can be detected. In this article, we review the characteristics of tumor vessels, tubulin-destabilizing mechanisms of VDAs, and in vivo effects of the VDAs that have been mostly studied in preclinical studies and clinical trials. We also compare the different tumor models adopted in the preclinical studies on VDAs. Multiparametric imaging biomarkers, mainly diffusion-weighted imaging and dynamic contrast-enhanced imaging from magnetic resonance imaging, are evaluated for their potential as morphological and functional imaging biomarkers for monitoring therapeutic effects of VDAs.

Does digital mammography in a decentralized breast cancer screening program lead to screening performance parameters comparable with film-screen mammography?

OBJECTIVE: To evaluate if the screening performance parameters of digital mammography (DM) in a decentralized screening organization were comparable with film-screen mammography (FSM). METHODS: A nationwide screening program was launched in 2001, and since 2005 screening with DM has been allowed. Firstly, the parameters of the three regional screening units (RSUs) that first switched to DM (11,355 women) were compared with the FSM period of the same three RSUs (23,325 women). Secondly, they were compared with the results of the whole central breast unit (CBU). RESULTS: The recall rate (RR) of the DM group in the initial round was 2.64% [2.40% for FSM (p = 0.43)] and in the subsequent round 1.20% [1.58% for FSM (p = 0.03)]. The cancer detection rate (CDR) was 0.59% for DM and 0.64% for FSM (p = 0.56). The percentage of ductal carcinoma in situ was 0.07% for DM and 0.16% for FSM (p = 0.02). The positive predictive value was high in the subsequent rounds (DM 48.00%, FSM 45.93%) and lower in the initial round (DM 24.05%, FSM 24.86%). Compared with the results of the whole CBU, DM showed no significant difference. CONCLUSION: DM can be introduced in a decentralized screening organization with a high CDR without increasing the RR.

Morphological, functional and metabolic imaging biomarkers: assessment of vascular-disrupting effect on rodent liver tumours.

OBJECTIVES: To evaluate effects of a vascular-disrupting agent on rodent tumour models. METHODS: Twenty rats with liver rhabdomyosarcomas received ZD6126 intravenously at 20 mg/kg, and 10 vehicle-treated rats were used as controls. Multiple sequences, including diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI) with the microvascular permeability constant (K), were acquired at baseline, 1 h, 24 h and 48 h post-treatment by using 1.5-T MRI. [(18)F]fluorodeoxyglucose micro-positron emission tomography ((18)F-FDG microPET) was acquired pre- and post-treatment. The imaging biomarkers including tumour volume, enhancement ratio, necrosis ratio, apparent diffusion coefficient (ADC) and K from MRI, and maximal standardised uptake value (SUV(max)) from FDG microPET were quantified and correlated with postmortem microangiography and histopathology. RESULTS: In the ZD6126-treated group, tumours grew slower with higher necrosis ratio at 48 h (P < 0.05), corresponding well to histopathology; tumour K decreased from 1 h until 24 h, and partially recovered at 48 h (P < 0.05), parallel to the evolving enhancement ratios (P < 0.05); ADCs varied with tumour viability and perfusion; and SUV(max) dropped at 24 h (P < 0.01). Relative K of tumour versus liver at 48 h correlated with relative vascular density on microangiography (r = 0.93, P < 0.05). CONCLUSIONS: The imaging biomarkers allowed morphological, functional and metabolic quantifications of vascular shutdown, necrosis formation and tumour relapse shortly after treatment. A single dose of ZD6126 significantly diminished tumour blood supply and growth until 48 h post-treatment.

Quantitative diffusion tensor imaging in amyotrophic lateral sclerosis: revisited.

Voxel-based analyses (VBA) are increasingly being used to detect white matter abnormalities with diffusion tensor imaging (DTI) in different types of pathologies. However, the validity, specificity, and sensitivity of statistical inferences of group differences to a large extent depend on the quality of the spatial normalization of the DTI images. Using high-dimensional nonrigid coregistration techniques that are able to align both the spatial and orientational diffusion information and incorporate appropriate templates that contain this complete DT information may improve this quality. Alternatively, a hybrid technique such as tract-based spatial statistics (TBSS) may improve the reliability of the statistical results by generating voxel-wise statistics without the need for perfect image alignment and spatial smoothing. In this study, we have used (1) a coregistration algorithm that was optimized for coregistration of DTI data and (2) a population-based DTI atlas to reanalyze our previously published VBA, which compared the fractional anisotropy and mean diffusivity maps of patients with amyotrophic lateral sclerosis (ALS) with those of healthy controls. Additionally, we performed a complementary TBSS analysis to improve our understanding and interpretation of the VBA results. We demonstrate that, as the overall variance of the diffusion properties is lowered after normalizing the DTI data with such recently developed techniques (VBA using our own optimized high-dimensional nonrigid coregistration and TBSS), more reliable voxel-wise statistical results can be obtained than had previously been possible, with our VBA and TBSS yielding very similar results. This study provides support for the view of ALS as a multisystem disease, in which the entire frontotemporal lobe is implicated.

Evaluation of clinical image processing algorithms used in digital mammography.

Screening is the only proven approach to reduce the mortality of breast cancer, but significant numbers of breast cancers remain undetected even when all quality assurance guidelines are implemented. With the increasing adoption of digital mammography systems, image processing may be a key factor in the imaging chain. Although to our knowledge statistically significant effects of manufacturer-recommended image processings have not been previously demonstrated, the subjective experience of our radiologists, that the apparent image quality can vary considerably between different algorithms, motivated this study. This article addresses the impact of five such algorithms on the detection of clusters of microcalcifications. A database of unprocessed (raw) images of 200 normal digital mammograms, acquired with the Siemens Novation DR, was collected retrospectively. Realistic simulated microcalcification clusters were inserted in half of the unprocessed images. All unprocessed images were subsequently processed with five manufacturer-recommended image processing algorithms (Agfa Musica 1, IMS Raffaello Mammo 1.2, Sectra Mamea AB Sigmoid, Siemens OPVIEW v2, and Siemens OPVIEW v1). Four breast imaging radiologists were asked to locate and score the clusters in each image on a five point rating scale. The free-response data were analyzed by the jackknife free-response receiver operating characteristic (JAFROC) method and, for comparison, also with the receiver operating characteristic (ROC) method. JAFROC analysis revealed highly significant differences between the image processings (F = 8.51, p < 0.0001), suggesting that image processing strongly impacts the detectability of clusters. Siemens OPVIEW2 and Siemens OPVIEW1 yielded the highest and lowest performances, respectively. ROC analysis of the data also revealed significant differences between the processing but at lower significance (F = 3.47, p = 0.0305) than JAFROC. Both statistical analysis methods revealed that the same six pairs of modalities were significantly different, but the JAFROC confidence intervals were about 32% smaller than ROC confidence intervals. This study shows that image processing has a significant impact on the detection of microcalcifications in digital mammograms. Objective measurements, such as described here, should be used by the manufacturers to select the optimal image processing algorithm.

Tumor models and specific contrast agents for small animal imaging in oncology.

Despite the widespread use of various imaging modalities in clinical and experimental oncology without or with combined application of commercially available nonspecific contrast agents (CAs), development of tissue- or organ- or disease-specific CAs has been a continuing effort for pursuing ever-improved sensitivity, specificity, and applicability. This is particularly true with magnetic resonance imaging (MRI) due to its intrinsic superb spatial/temporal/contrast resolutions and adequate detectability for tiny amount of substances. In this context, research using small animal tumor models has played an indispensible role in preclinical exploration of tissue specific CAs. Emphasizing more on methodological and practical aspects, this article aims to share our cumulated experiences on how to create tumor models for evaluation and development of new tissue specific MRI CAs and how to apply such models in imaging-based research studies. With the results that are repeatedly confirmed by later clinical applications in cancer patients, some of our early preclinical studies have contributed to the designs of subsequent clinical trials on the new CAs, some studies have predicted new utilities of these CAs; and other studies have led to the discoveries of new tissue- or disease-specific CAs with novel diagnostic or even therapeutic potentials. Among commonly adopted tumor models, the chemically induced and surgically implanted nodules in the liver prove very useful to simulate primary and metastatic intrahepatic tumors, respectively in clinical patients. The methods to create tumor models have eased procedures and yielded high success rates. The specific properties of the new CAs could be outshined by intraindividual comparison to the commercial CAs as nonspecific controls. Meticulous imaging-microangiography-histology matching techniques guaranteed colocalization of the lesion on in vivo MRI and postmortem tissue specimen, hence correct imaging interpretation and longstanding conclusions. As exemplified in the real study cases, the present experimental set-up proves applicable in small animals for imaging-based oncological investigations, and may provide a platform for the currently booming molecular imaging in a multimodality environment.

Diffusion-weighted MRI of hepatic tumor in rats: comparison between in vivo and postmortem imaging acquisitions.

PURPOSE: To determine the feasibility of in vivo diffusion-weighted imaging (DWI) to distinguish between normal liver, viable tumor and necrosis compared to postmortem DWI in a rat model with vascular-targeting treatment. MATERIALS AND METHODS: Fifteen rats with liver implantation of 30 rhabdomyosarcomas were treated with combretastatin A-4-phosphate (CA4P) at 10 mg/kg. Two days after treatment, T2-weighted imaging, precontrast T1-weighted imaging, postcontrast T1-weighted imaging, and DWI were performed in vivo and postmortem with a 1.5T scanner. Apparent diffusion coefficients (ADCs) calculated from DWIs with b values of 0, 50, and 100 seconds/mm2 (ADClow), 500, 750, and 1000 seconds/mm2 (ADChigh), 0, 500, and 1000 seconds/mm2 (ADC3b), and 0-1000 seconds/mm2 (ADC10b) for tumor, liver, therapeutic necrosis, and phantoms were compared and validated with ex vivo microangiographic and histopathologic findings. RESULTS: Except ADClow between tumor and necrosis, in vivo ADCs successfully differentiated liver, viable tumor, and necrosis (P<0.05). Compared to in vivo outcomes, postmortem ADCs significantly dropped in tumor and liver (P<0.05) except ADChigh of tumor, but not in necrosis and phantoms. Compared to ADClow, ADChigh was less affected by vital status. CONCLUSION: Advantageous over postmortem DWI, in vivo DWI provides a noninvasive easy-performing tool for distinguishing between liver, viable tumor, and necrosis. ADClow and ADChigh better reflect tissue perfusion and water diffusion, respectively.

Treatment of rodent liver tumor with combretastatin a4 phosphate: noninvasive therapeutic evaluation using multiparametric magnetic resonance imaging in correlation with microangiography and histology.

OBJECTIVES: To document tumoricidal events after intravenous administration of a vascular targeting agent combretastatin A-4-phosphate (CA4P) in rodent liver tumors by using multiparametric magnetic resonance imaging (MRI) in correlation with microangiography and histopathology. MATERIALS AND METHODS: Thirty rhabdomyosarcomas of 8 to 14 mm in diameter were obtained 16 days after implantation in liver lobes of 15 rats. Using a 1.5T magnet and a 4-channel wrist coil, T2-weighted imaging (T2WI), pre- and postcontrast T1-weighted imaging (T1WI), diffusion-weighted imaging (DWI), and dynamic susceptibility imaging (DSI) with relative blood volume (rBV) and flow (rBF) maps were acquired at baseline, 1 hour, 6 hours, and 48 hours after iv injection of CA4P at 10 mg/kg and vehicle in 9 treated and 6 control rats, respectively. In vivo data including signal intensity (SI), tumor volume, apparent diffusion coefficient (ADC), rBV, and rBF were correlated with ex vivo microangiographic and histopathologic findings. RESULTS: CA4P-treated tumors (n = 18) grew slower than those (n = 12) of controls (P < 0.05), with vascular shutdown evident on CE-T1WI at 1 hour but more prominent at 6 hours. However, enhanced rim occurred in the periphery 48 hours after treatment, indicating neovascularization. ADC map enabled distinction between necrotic and viable tumors. DSI-derived tumoral rBV and rBF decreased significantly at 1 hour through 6 hours and partly recovered at 48 hours. SI-time curve reflected diverse therapeutic responses between tumor and liver. MRI findings were verified by ex vivo techniques. CONCLUSIONS: Clinical MRI allowed monitoring of CA4P-related vascular shutdown, necrosis, and neovascularization of liver tumors in rats. Single dose of CA4P seemed insufficient for tumor eradication because of evident peripheral residue and recurrence.

A modified rabbit model of reperfused myocardial infarction for cardiac MR imaging research.

We sought to obtain a rabbit myocardial infarction (MI) model for research with cardiac magnetic resonance imaging (cMRI) by overcoming a few technical difficulties. A novel endotracheal method was developed for intubation and ventilation. Fourteen rabbits were divided into group-1 (n = 8) with open-chest occlusion of left circumflex coronary artery and closed-chest reperfusion, and group-2 (n = 6) of non-ischemic control; and received ECG-triggered cMRI with delayed contrast enhancement (DE-cMRI) at a 1.5 T clinical scanner. The MI areas in group-1 were morphometrically compared between DE-cMRI and histochemically stained specimens. Left ventricular (LV) functions were compared between two groups.The success rate of intubation and reperfused MI was 8/8 and 6/8, respectively. Global and regional LV functions significantly decreased in group-1 as evidenced by significant hypokinesis of lateral LV-wall and wall thickening (P \ 0.001). Mean MI-area was 19.41 +/- 21.92% on DE-cMRI and 19.10 +/- 22.61% with histochemical staining (r = 0.985). Global MI-volume was 17.92 +/- 7.42% on DE-cMRI and 16.62 +/- 7.16% with histochemistry (r = 0.994). The usefulness of this model was successfully tested for assessing a new contrast agent. The present rabbit MI model may offer a practical platform for more translational research using clinical MRI-facilities.