Predicting response to neoadjuvant chemotherapy with liquid biopsies and multiparametric MRI in patients with breast cancer.

Accurate prediction of response to neoadjuvant chemotherapy (NAC) can help tailor treatment to individual patients' needs. Little is known about the combination of liquid biopsies and computer extracted features from multiparametric magnetic resonance imaging (MRI) for the prediction of NAC response in breast cancer. Here, we report on a prospective study with the aim to explore the predictive potential of this combination in adjunct to standard clinical and pathological information before, during and after NAC. The study was performed in four Dutch hospitals. Patients without metastases treated with NAC underwent 3 T multiparametric MRI scans before, during and after NAC. Liquid biopsies were obtained before every chemotherapy cycle and before surgery. Prediction models were developed using penalized linear regression to forecast residual cancer burden after NAC and evaluated for pathologic complete response (pCR) using leave-one-out-cross-validation (LOOCV). Sixty-one patients were included. Twenty-three patients (38%) achieved pCR. Most prediction models yielded the highest estimated LOOCV area under the curve (AUC) at the post-treatment timepoint. A clinical-only model including tumor grade, nodal status and receptor subtype yielded an estimated LOOCV AUC for pCR of 0.76, which increased to 0.82 by incorporating post-treatment radiological MRI assessment (i.e., the "clinical-radiological" model). The estimated LOOCV AUC was 0.84 after incorporation of computer-extracted MRI features, and 0.85 when liquid biopsy information was added instead of the radiological MRI assessment. Adding liquid biopsy information to the clinical-radiological resulted in an estimated LOOCV AUC of 0.86. In conclusion, inclusion of liquid biopsy-derived markers in clinical-radiological prediction models may have potential to improve prediction of pCR after NAC in breast cancer.

MRI to assess response after neoadjuvant chemotherapy in breast cancer subtypes: a systematic review and meta-analysis.

This meta-analysis aimed to estimate and compare sensitivity, specificity, positive- (PPV) and negative predictive value (NPV) of magnetic resonance imaging (MRI) for predicting pathological complete remission (pCR) after neoadjuvant chemotherapy (NAC) in patients with early-stage breast cancer. We stratified for molecular subtype by immunohistochemistry (IHC) and explored the impact of other factors. Two researchers systematically searched PUBMED and EMBASE to select relevant studies and extract data. For meta-analysis of sensitivity and specificity, we used bivariate random-effects models. Twenty-six included studies contained 4497 patients. There was a significant impact of IHC subtype on post-NAC MRI accuracy (p = 0.0082) for pCR. The pooled sensitivity was 0.67 [95% CI 0.58-0.74] for the HR-/HER2-, 0.65 [95% CI 0.56-0.73] for the HR-/HER2+, 0.55 [95% CI 0.45-0.64] for the HR+/HER2- and 0.60 [95% CI 0.50-0.70] for the HR+/HER2+ subtype. The pooled specificity was 0.85 [95% CI 0.81-0.88] for the HR-/HER2-, 0.81 [95% CI 0.74-0.86] for the HR-/HER2+, 0.88[95% CI 0.84-0.91] for the HR+/HER2- and 0.74 [95% CI 0.63-0.83] for the HR+/HER2+ subtype. The PPV was highest in the HR-/HER2- subtype and lowest in the HR+/HER2- subtype. MRI field strength of 3.0 T was associated with a higher sensitivity compared to 1.5 T (p = 0.00063). The accuracy of MRI for predicting pCR depends on molecular subtype, which should be taken into account in clinical practice. Higher MRI field strength positively impacts accuracy. When intervention trials based on MRI response evaluation are designed, the impact of IHC subtype and field strength on MR accuracy should be considered.

Population-based estimates of overtreatment with adjuvant systemic therapy in early breast cancer patients with data from the Netherlands and the USA.

PURPOSE: Although adjuvant systemic therapy (AST) helps increase breast cancer-specific survival (BCSS), there is a growing concern for overtreatment. By estimating the expected BCSS of AST using PREDICT, this study aims to quantify the number of patients treated with AST without benefit to provide estimates of overtreatment. METHODS: Data of all non-metastatic unilateral breast cancer patients diagnosed in 2015 were retrieved from cancer registries from The Netherlands and the USA. The PREDICT tool was used to estimate AST survival benefit. Overtreatment was defined as the proportion of patients that would have survived regardless of or died despite AST within 10 years. Three scenarios were evaluated: actual treatment, and recommendations by the Dutch or USA guidelines. RESULTS: 59.5% of Dutch patients were treated with AST. 6.4% (interquartile interval [IQI] = 2.5, 8.2%) was expected to survive at least 10 years due to AST, leaving 93.6% (IQI = 91.8, 97.5%) without AST benefit (overtreatment). The lowest expected amount of overtreatment was in the targeted and chemotherapy subgroup, with 86.5% (IQI = 83.4, 89.6%) overtreatment, and highest in the only endocrine treatment subgroup, with 96.7% (IQI = 96.0, 98.1%) overtreatment. Similar results were obtained using data from the USA, and guideline recommendations. CONCLUSION: Based on PREDICT, AST prevents 10-year breast cancer death in 6.4% of the patients treated with AST. Consequently, AST yields no survival benefit to many treated patients. Especially improved personalization of endocrine therapy is relevant, as this therapy is widely used and is associated with the highest amount of overtreatment.

Preoperative indication for systemic therapy extended to patients with early-stage breast cancer using multiparametric 7-tesla breast MRI.

PURPOSE: To establish a preoperative decision model for accurate indication of systemic therapy in early-stage breast cancer using multiparametric MRI at 7-tesla field strength. MATERIALS AND METHODS: Patients eligible for breast-conserving therapy were consecutively included. Patients underwent conventional diagnostic workup and one preoperative multiparametric 7-tesla breast MRI. The postoperative (gold standard) indication for systemic therapy was established from resected tumor and lymph-node tissue, based on 10-year risk-estimates of breast cancer mortality and relapse using Adjuvant! Online. Preoperative indication was estimated using similar guidelines, but from conventional diagnostic workup. Agreement was established between preoperative and postoperative indication, and MRI-characteristics used to improve agreement. MRI-characteristics included phospomonoester/phosphodiester (PME/PDE) ratio on 31-phosphorus spectroscopy (31P-MRS), apparent diffusion coefficients on diffusion-weighted imaging, and tumor size on dynamic contrast-enhanced (DCE)-MRI. A decision model was built to estimate the postoperative indication from preoperatively available data. RESULTS: We included 46 women (age: 43-74yrs) with 48 invasive carcinomas. Postoperatively, 20 patients (43%) had positive, and 26 patients (57%) negative indication for systemic therapy. Using conventional workup, positive preoperative indication agreed excellently with positive postoperative indication (N = 8/8; 100%). Negative preoperative indication was correct in only 26/38 (68%) patients. However, 31P-MRS score (p = 0.030) and tumor size (p = 0.002) were associated with the postoperative indication. The decision model shows that negative indication is correct in 21/22 (96%) patients when exempting tumors larger than 2.0cm on DCE-MRI or with PME>PDE ratios at 31P-MRS. CONCLUSIONS: Preoperatively, positive indication for systemic therapy is highly accurate. Negative indication is highly accurate (96%) for tumors sized ≤2,0cm on DCE-MRI and with PME≤PDE ratios on 31P-MRS.

Eigentumors for prediction of treatment failure in patients with early-stage breast cancer using dynamic contrast-enhanced MRI: a feasibility study.

We present a radiomics model to discriminate between patients at low risk and those at high risk of treatment failure at long-term follow-up based on eigentumors: principal components computed from volumes encompassing tumors in washin and washout images of pre-treatment dynamic contrast-enhanced (DCE-) MR images. Eigentumors were computed from the images of 563 patients from the MARGINS study. Subsequently, a least absolute shrinkage selection operator (LASSO) selected candidates from the components that contained 90% of the variance of the data. The model for prediction of survival after treatment (median follow-up time 86 months) was based on logistic regression. Receiver operating characteristic (ROC) analysis was applied and area-under-the-curve (AUC) values were computed as measures of training and cross-validated performances. The discriminating potential of the model was confirmed using Kaplan-Meier survival curves and log-rank tests. From the 322 principal components that explained 90% of the variance of the data, the LASSO selected 28 components. The ROC curves of the model yielded AUC values of 0.88, 0.77 and 0.73, for the training, leave-one-out cross-validated and bootstrapped performances, respectively. The bootstrapped Kaplan-Meier survival curves confirmed significant separation for all tumors (P < 0.0001). Survival analysis on immunohistochemical subgroups shows significant separation for the estrogen-receptor subtype tumors (P < 0.0001) and the triple-negative subtype tumors (P = 0.0039), but not for tumors of the HER2 subtype (P = 0.41). The results of this retrospective study show the potential of early-stage pre-treatment eigentumors for use in prediction of treatment failure of breast cancer.

Dual-head gamma camera system for intraoperative localization of radioactive seeds.

Breast-conserving surgery is a standard option for the treatment of patients with early-stage breast cancer. This form of surgery may result in incomplete excision of the tumor. Iodine-125 labeled titanium seeds are currently used in clinical practice to reduce the number of incomplete excisions. It seems likely that the number of incomplete excisions can be reduced even further if intraoperative information about the location of the radioactive seed is combined with preoperative information about the extent of the tumor. This can be combined if the location of the radioactive seed is established in a world coordinate system that can be linked to the (preoperative) image coordinate system. With this in mind, we propose a radioactive seed localization system which is composed of two static ceiling-suspended gamma camera heads and two parallel-hole collimators. Physical experiments and computer simulations which mimic realistic clinical situations were performed to estimate the localization accuracy (defined as trueness and precision) of the proposed system with respect to collimator-source distance (ranging between 50 cm and 100 cm) and imaging time (ranging between 1 s and 10 s). The goal of the study was to determine whether or not a trueness of 5 mm can be achieved if a collimator-source distance of 50 cm and imaging time of 5 s are used (these specifications were defined by a group of dedicated breast cancer surgeons). The results from the experiments indicate that the location of the radioactive seed can be established with an accuracy of 1.6 mm ± 0.6 mm if a collimator-source distance of 50 cm and imaging time of 5 s are used (these experiments were performed with a 4.5 cm thick block phantom). Furthermore, the results from the simulations indicate that a trueness of 3.2 mm or less can be achieved if a collimator-source distance of 50 cm and imaging time of 5 s are used (this trueness was achieved for all 14 breast phantoms which were used in this study). Based on these results we conclude that the proposed system can be a valuable tool for (real-time) intraoperative breast cancer localization.

Neoadjuvant chemotherapy adaptation and serial MRI response monitoring in ER-positive HER2-negative breast cancer.

BACKGROUND: Changing the neoadjuvant chemotherapy regimen in insufficiently responding breast cancer is not a standard policy. We analysed a series of patients with 'luminal'-type breast cancer in whom the second half of neoadjuvant chemotherapy was selected based on the response to the first half. METHODS: Patients with oestrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer received three courses of neoadjuvant dose-dense doxorubicin and cyclophosphamide (ddAC). Three further courses of ddAC were administered in case of a 'favourable response' on the interim magnetic resonance imaging (MRI) and a switch to docetaxel and capecitabine (DC) was made in case of an 'unfavourable response', using previously published response criteria. The efficacy of this approach was evaluated by tumour size reductions on serial contrast-enhanced MRI, pathologic response and relapse-free survival. RESULTS: Two hundred and forty-six patients received three courses of ddAC. One hundred and sixty-four patients (67%) had a favourable response at the interim MRI, with a mean tumour size reduction of 31% after the first three courses and 34% after the second three courses. Patients with unfavourable responsive tumours had a mean tumour size reduction of 12% after three courses and received three courses of DC rather than ddAC. This led to a mean shrinkage of 27%. CONCLUSION: The tumour size reduction of initially less responsive tumours after treatment adaptation adds further evidence that a response-adapted strategy may enhance the efficacy of neoadjuvant chemotherapy.

Fully automated deformable registration of breast DCE-MRI and PET/CT.

Accurate characterization of breast tumors is important for the appropriate selection of therapy and monitoring of the response. For this purpose breast imaging and tissue biopsy are important aspects. In this study, a fully automated method for deformable registration of DCE-MRI and PET/CT of the breast is presented. The registration is performed using the CT component of the PET/CT and the pre-contrast T1-weighted non-fat suppressed MRI. Comparable patient setup protocols were used during the MRI and PET examinations in order to avoid having to make assumptions of biomedical properties of the breast during and after the application of chemotherapy. The registration uses a multi-resolution approach to speed up the process and to minimize the probability of converging to local minima. The validation was performed on 140 breasts (70 patients). From a total number of registration cases, 94.2% of the breasts were aligned within 4.0 mm accuracy (1 PET voxel). Fused information may be beneficial to obtain representative biopsy samples, which in turn will benefit the treatment of the patient.

Association of primary tumour FDG uptake with clinical, histopathological and molecular characteristics in breast cancer patients scheduled for neoadjuvant chemotherapy.

PURPOSE: The aim of this study was to evaluate the association of primary tumour (18)F-fluorodeoxyglucose (FDG) uptake with clinical, histopathological and molecular characteristics of breast cancer patients scheduled for neoadjuvant chemotherapy. Second, we wished to establish for which patients pretreatment positron emission tomography (PET)/CT could safely be omitted because of low FDG uptake. METHODS: PET/CT was performed in 214 primary stage II or III breast cancer patients in the prone position with hanging breasts. Tumour FDG uptake was qualitatively evaluated to determine the possibility of response monitoring with PET/CT and was quantitatively assessed using maximum standardized uptake values (SUV(max)). FDG uptake was compared with age, TNM stage, histology, hormone and human epidermal growth factor receptor 2 status, grade, Ki-67 and molecular subtype in univariable and multivariable analyses. RESULTS: In 203 tumours (95 %) FDG uptake was considered sufficient for response monitoring. No subgroup of patients with consistently low tumour FDG uptake could be identified. In a univariable analysis, SUV(max) was significantly higher in patients with distant metastases at staging examination, non-lobular carcinomas, tumours with negative hormone receptors, triple negative tumours, grade 3 tumours, and in tumours with a high proliferation index (Ki-67 expression). After multiple linear regression analysis, triple negative and grade 3 tumours were significantly associated with a higher SUV(max). CONCLUSION: Primary tumour FDG uptake in breast cancer patients scheduled for neoadjuvant chemotherapy is significantly higher in tumours with prognostically unfavourable characteristics. Based on tumour characteristics associated with low tumour FDG uptake, this study was unable to identify a subgroup of patients unlikely to benefit from pretreatment PET/CT.

Excised and irradiated volumes in relation to the tumor size in breast-conserving therapy.

In early-stage breast cancer and DCIS patients, breast-conserving therapy is today's standard of care. The purpose of this study was to evaluate the relation between the microscopic tumor diameter (mTD), the excised specimen (ES) volume, and the irradiated postoperative complex (POC) volume, in patients treated with breast-conserving therapy. In 186 patients with pTis-2N0 breast cancer, the mTDs, ES, and POC volumes (as delineated on the radiotherapy-planning CT scan), were retrospectively determined. Linear regression analysis was performed to study the association between the mTD, and the ES and POC volumes. The explained variance (r (2)) was calculated to establish the proportion of variation in the outcome variable that could be explained by the determinant (P ≤ 0.05). Moreover, the influence of tumor characteristics, age, surgical procedures, and breast size was studied. Median mTD was 1.2 cm (range 0.1-3.6 cm), median ES volume was 60 cm(3) (range 6-230 cm(3)) and median POC volume was 15 cm(3) (range 0.5-374 cm(3)). The POC was not clearly visible on the majority of the CT scans, based on a median assigned cavity visualization score of 3 (range 1-5). The explained variance for the mTD on the ES volume was low (r(2) = 0.08, P < 0.001). A slightly stronger association was observed in palpable tumors (r(2) = 0.23, P < 0.001) and invasive lobular carcinomas (r(2) = 0.39, P = 0.01). Furthermore, weak associations were observed between POC volume and mTD (r(2) = 0.04, P = 0.01), and POC and ES volume (r(2) = 0.23, P < 0.001). A weak association was observed between breast volume and ES volume (r(2) = 0.27, P < 0.001). In conclusion, both the excised and the irradiated POC volumes did not show a clinically relevant association with the mTD in women with early-stage breast cancer treated with breast-conserving therapy. Future studies should focus on improvement of surgical localization, development of image-guided, minimally invasive operation techniques, and more accurate image-guided target volume delineation in radiotherapy.

The impact of preoperative breast MRI on the re-excision rate in invasive lobular carcinoma of the breast.

Re-excision rates after breast conserving surgery(BCS) of invasive lobular carcinoma (ILC) are high.Preoperative breast MRI has the potential to reduce re-excision rates, but may lead to an increased rate of mastectomies. Hence, we assessed the influence of preoperative breast MRI on the re-excision rate and the rate of mastectomies. We performed a retrospective cohort study of a consecutive series of patients with ILC who presented in one of two dedicated tertiary cancer centers between 1993 and 2005. We assessed the initial type of surgery(BCS or mastectomy), the re-excision rate and the final type of surgery. Patients were stratified into two groups:those who received preoperative MRI (MR? group) and those who did not (MR- group). In the MR- group, 27%of the patients underwent a re-excision after initial BCS. In the MR? group, this rate was significantly lower at 9%.The odds ratio was 3.64 (95% CI: 1.30-10.20, P = 0.010).There was a trend towards a lower final mastectomy rate in the MR? group compared to the MR- group (48 vs. 59%,P = 0.098). In conclusion, preoperative MRI in patients with ILC can reduce re-excision rates without increasing the rate of mastectomies.

Analysis of the relative deformation of lung lobes before and after surgery in patients with NSCLC.

An accurate assessment of the extent of the tumor is critical for successful local treatment of lung cancer by surgery and/or radiotherapy. Guidelines to establish the extent of treatment margins may be derived from correlation studies between pre-treatment imaging and histopathology. Deformations occur, however, between in-vivo CT imaging and ex-vivo pathology due to the softness of lung tissue and pathology processing. The first aim of this study was to quantify these deformations in tissue around non-small cell lung cancer. The second aim was to explore factors associated with the magnitude of the deformations. The study was performed in 25 patients who underwent lobectomy after preoperative CT. Non-rigid registration was employed to evaluate tissue deformations around the gross tumor volume (GTV), taking into account potential differences in elasticity between tumor and healthy lung tissue. Tissue was found to be compacted by approximately 60% depending on circularity of the tumor and orientation of the specimen on the pathology table during processing. The deformations give rise to potential underestimation of the treatment margins in pathology studies that do not take this aspect into account.

The impact of preoperative MRI on breast-conserving surgery of invasive cancer: a comparative cohort study.

AIM: To assess whether preoperative contrast-enhanced magnetic resonance imaging (MRI) of the breast influences the rate of incomplete tumor excision. METHODS: In a cohort of 349 women with invasive breast cancer, patients eligible for breast-conserving therapy (BCT) on the basis of conventional imaging and palpation only (N = 176) were compared to those who had an additional preoperative MRI (N = 173). Multivariate analysis was applied to explore associations with incomplete tumor excision. RESULTS: MRI detected larger extent of breast cancer in 19 women (11.0%), leading to treatment change: mastectomy (8.7%) or wider excision (2.3%). Tumor excision was incomplete in 22/159 (13.8%) wide local excisions in the MRI group and in 35/180 (19.4%) in the non-MRI group (P = 0.17). Stratified to tumor type, incompletely excised infiltrating ductal carcinoma (IDC) was significantly associated with absence of MRI: 11/136 (8.1%) versus 2/126 (1.6%) (MRI present) (P = 0.02). No significant factors explained incomplete excision of other tumor types. CONCLUSION: Preoperative MRI did not significantly affect the overall rate of incomplete tumor excision, but it yielded significantly lower rate of incompletely excised IDC. The reduction of incomplete excisions after MRI was smaller than the rate of a prior treatment change incurred by MRI.

[Neoadjuvant systemic therapy in patients with operable primary breast cancer: more benefits than breast-conserving therapy]. / Neoadjuvante systemische therapie bij het primair operabel mammacarcinoom: meer voordelen dan alleen borstsparende behandeling.

OBJECTIVE: To analyse the extent to which primary systemic therapy (PST) achieves the main goals in patients with operable primary breast cancer, these goals being breast-conserving therapy and pathological complete remission (pCR), and to evaluate the response. DESIGN: Retrospective. METHOD: In a retrospective analysis of 254 patients treated with PST in 2000-2007 in the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, patients with inoperable disease (T4 and/or N3) were excluded. The response was mostly evaluated using contrast-enhanced MRI, whereby the chemotherapy regimen was switched if the reduction in the largest diameter of contrast washout was less than 25%. pCR was defined as no evidence of invasive cancer in the breast and axilla in the resection specimen. RESULTS: In patients with ductal carcinoma and lobular carcinoma an increase in breast-conserving therapy was seen in 32% and 17% of patients respectively. The pCR rate was 12% and 2% respectively. Secondary mastectomy because of irradical resection was required in 3% and 50% respectively. Multivariate analysis indicated that molecular type, defined on the basis of the expression of hormone receptors and human epidermal growth factor receptor 2 (HER2), i.e. luminal (oestrogen receptor-positive), basal (hormone receptor-negative and HER2-negative) and HER2-positive tumours treated with trastuzumab was the only independent predictor of pCR; 2%, 28% and 35% respectively (p=0.004). In 43 patients the chemotherapy regimen was adjusted because the tumour did not respond sufficiently. A favourable clinical response was observed in 72% (31/43) of these patients. CONCLUSION: The observed increase in the number of breast-conserving therapies after PST was clinically relevant. PST may be more effective when contrast-enhanced MRI is used for interim evaluation, based on which the treatment may be switched. There was a clear difference in histological and molecular types of tumour and therefore the choice of treatment may be adjusted accordingly.

Reduction in the number of sentinel lymph node procedures by preoperative ultrasonography of the axilla in breast cancer.

Currently, breast cancer patients without clinically suspicious lymph nodes are candidates for sentinel lymph node procedures (SLNPs). The aims of this study were to investigate whether preoperative axillary ultrasonography and fine-needle aspiration cytology (FNA) can reduce the number of the more time-consuming SLNPs, and to identify a subset of quantitative nodal features to predict metastatic involvement. 268 axillae were ultrasonographically examined. FNA was performed on suspicious nodes (smallest diameter > or =5 mm or atypical cortex appearance). SLNP was omitted if a tumour-positive node was found on FNA. Length, width, maximum cortex thickness and appearance of cortex and hilus were ultrasonographically established. In 93 axillae (35%), at least one node was detected with ultrasound. FNA was performed once per axilla on 66 nodes; 37 (56%) contained tumour cells. 31% of all tumour-positive axillae (macro-+micrometastases) was found by ultrasound and FNA (37/121). 41% of all axillae containing macrometastases was found by ultrasound and FNA (36/87). SLNPs were reduced by 14% (37/268). Maximum cortex thickness is the main feature to predict metastatic involvement (area under Receiver Operating Characteristic (ROC) curve (A(Z))=0.87).

Displacement of breast tissue and needle deviations during stereotactic procedures.

RATIONALE AND OBJECTIVES: The aim of this study was to quantify the displacement of breast tissue and the inaccuracy of needle positioning for biopsy (14-gauge) and localization (19.5-gauge) needles. METHODS: For displacement of breast tissue, differences between the coordinates of identifiable microcalcifications in the images before (baseline) and after needle positioning were analyzed (n = 52). For accuracy of needle positioning, differences between the coordinates of the needle tip and the target were analyzed in breast tissue (n = 97) and in air (n = 246). RESULTS: Average target displacement was 2.1 mm for biopsy needles (95% prediction interval [PI] 0.6-7.8) and 1.0 mm (95% PI 0.3-3.9) for localization needles. Mean inaccuracy of needle positioning in breast tissue was 1.1 mm (95% PI 0.4-3.0) and 1.8 mm (95% PI 0.7-4.6) for biopsy and localization needles, respectively. CONCLUSIONS: Tissue and needle displacements cause a total positioning error of 2.4 mm in stereotactic core biopsy, which will limit the attainable diagnostic accuracy.

Accurate measurement of the dynamic response of a scanning electronic portal imaging device.

An important condition for the safe introduction of dynamic intensity modulated radiotherapy (IMRT) using a multileaf collimator (MLC) is the ability to verify the leaf trajectories. In order to verify IMRT using an electronic portal imaging device (EPID), the EPID response should be accurate and fast. Noninstantaneous dynamic response causes motion blurring. The aim of this study is to develop a measurement method to determine the magnitude of the geometrical error as a result of motion blurring for imagers with scanning readout. The response of a liquid-filled ionization chamber EPID, as an example of a scanning imager, on a moving beam is compared with the response of a diode placed at the surface of the EPID. The signals are compared under the assumption that all EPID rows measure the same dose rate when a straight moving field edge is imaged. The measurements are performed at several levels of attenuation to investigate the influence of dose rate on the response of the detector. The accuracy of the measurement method is better than 0.25 mm. We found that the liquid-filled ionization chamber EPID does not suffer from significant motion blurring under clinical circumstances. Using a maximum gradient edge detector to determine the field edge in an image obtained by a liquid-filled ionization chamber EPID, errors smaller than 1 mm are found at a dose rate of 105 MU/min and a field edge speed of 1.1 cm/s. The errors reduce at higher dose rates. The presented method is capable of quantifying the geometrical errors in determining the position of the edge of a moving field with subpixel accuracy. The errors in field edge position determined by a liquid-filled ionization chamber EPID are negligible in clinical practice. Consequently, these EPIDs are suitable for geometric IMRT verification, as far as dynamic response is concerned.

Computerized analysis of breast lesions in three dimensions using dynamic magnetic-resonance imaging.

Contrast-enhanced magnetic resonance imaging (MRI) of the breast is known to reveal breast cancer with higher sensitivity than mammography alone. The specificity is, however, compromised by the observation that several benign masses take up contrast agent in addition to malignant lesions. The aim of this study is to increase the objectivity of breast cancer diagnosis in contrast-enhanced MRI by developing automated methods for computer-aided diagnosis. Our database consists of 27 MR studies from 27 patients. In each study, at least four MR series of both breasts are obtained using FLASH three-dimensional (3D) acquisition at 90 s time intervals after injection of Gadopentetate dimeglumine (Gd-DTPA) contrast agent. Each series consists of 64 coronal slices with a typical thickness of 2 mm, and a pixel size of 1.25 mm. The study contains 13 benign and 15 malignant lesions from which features are automatically extracted in 3D. These features include margin descriptors and radial gradient analysis as a function of time and space. Stepwise multiple regression is employed to obtain an effective subset of combined features. A final estimate of likelihood of malignancy is determined by linear discriminant analysis, and the performance of classification by round-robin testing and receiver operating characteristics (ROC) analysis. To assess the efficacy of 3D analysis, the study is repeated in two-dimensions (2D) using a representative slice through the middle of the lesion. In 2D and in 3D, radial gradient analysis and analysis of margin sharpness were found to be an effective combination to distinguish between benign and malignant masses (resulting area under the ROC curve: 0.96). Feature analysis in 3D was found to result in higher performance of lesion characterization than 2D feature analysis for the majority of single and combined features. In conclusion, automated feature extraction and classification has the potential to complement the interpretation of radiologists in an objective, consistent, and accurate way.

Effect of image artifacts, organ motion, and poor segmentation on the reliability and accuracy of three-dimensional chamfer matching.

Our objective was to investigate the influence of various image artifacts on three-dimensional chamfer matching. A number of artificial and natural artifacts (for instance, as a model for CT-MR matching) were introduced or suppressed in pairs of pelvic CT scans, and a perturbation study was used to determine reliability and accuracy in a well known ground truth situation. In general, chamfer matching is extremely robust against missing data, low resolution, and poor segmentation of the images. In the presence of artifacts, minimization of the average distance outperformed minimization of the root-mean-square distance. Outliers in the scan from which the point list is obtained must be avoided. For example, rotation of the femurs reduces CT-CT registration accuracy by 1-2 mm. The robustness of chamfer matching is confirmed by a limited perturbation study of CT-MR registration for the pelvic region. In conclusion, chamfer matching is extremely accurate and reliable if outliers are avoided in the scan from which the point list is derived, and the average distance is used as a cost function.

Automatic three-dimensional inspection of patient setup in radiation therapy using portal images, simulator images, and computed tomography data.

In external beam radiotherapy, conventional analysis of portal images in two dimensions (2D) is limited to verification of in-plane rotations and translations of the patient. We developed and clinically tested a new method for automatic quantification of the patient setup in three dimensions (3D) using one set of computed tomography (CT) data and two transmission images. These transmission images can be either a pair of simulator images or a pair of portal images. Our procedure adjusts the position and orientation of the CT data in order to maximize the distance through bone in the CT data along lines between the focus of the irradiation unit and bony structures in the transmission images. For this purpose, bony features are either automatically detected or manually delineated in the transmission images. The performance of the method was quantified by aligning randomly displaced CT data with transmission images simulated from digitally reconstructed radiographs. In addition, the clinical performance were assessed in a limited number of images of prostate cancer and parotid gland tumor treatments. The complete procedure takes less than 2 min on a 90-MHz Pentium PC. The alignment time is 50 s for portal images and 80 s for simulator images. The accuracy is about 1 mm and 1 degrees. Application to clinical cases demonstrated that the procedure provides essential information for the correction of setup errors in case of large rotations (typically larger than 2 degrees) in the setup. The 3D procedure was found to be robust for imperfections in the delineation of bony structures in the transmission images. Visual verification of the results remains, however, necessary. It can be concluded that our strategy for automatic analysis of patient setup in 3D is accurate and robust. The procedure is relatively fast and reduces the human workload compared with existing techniques for the quantification of patient setup in 3D. In addition, the procedure improves the accuracy of treatment verification in 2D in some cases where rotational deviations in the setup occur.