K. Gilhuijs

Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer

We have studied in vivo responses of “spontaneous” Brca1- and p53-deficient mammary tumors arising in conditional mouse mutants to treatment with doxorubicin, docetaxel, or cisplatin. Like human tumors, the response of individual mouse tumors varies, but eventually they all become resistant to the maximum tolerable dose of doxorubicin or docetaxel. The tumors also respond well to cisplatin but do not become resistant, even after multiple treatments in which tumors appear to regrow from a small fraction of surviving cells. Classical biochemical resistance mechanisms, such as up-regulated drug transporters, appear to be responsible for doxorubicin resistance, rather than alterations in drug-damage effector pathways. Our results underline the promise of these mouse tumors for the study of tumor-initiating cells and of drug therapy of human cancer.

Ultrasonography and Fine-Needle Aspiration Cytology Can Spare Breast Cancer Patients Unnecessary Sentinel Lymph Node Biopsy

BackgroundSome 30% to 40% of the breast cancer patients scheduled for sentinel node biopsy have axillary metastasis. Pilot studies suggest that ultrasonography is useful in the preoperative detection of such nodes. The aims of this study were to evaluate the sensitivity of preoperative ultrasonography and fine-needle aspiration cytology for detecting axillary metastases and to assess how often sentinel node biopsy could be avoided.MethodsBetween October 1999 and December 2003, 726 patients with clinically negative lymph nodes were eligible for sentinel node biopsy. A total of 732 axillae were examined. Preoperative ultrasonography with subsequent fine-needle aspiration cytology in case of suspicious lymph nodes was performed in all patients. The sentinel node procedure was omitted in patients with tumor-positive axillary lymph nodes in lieu of axillary lymph node dissection.ResultsUltrasound and fine-needle aspiration cytology established axillary metastases in 58 (8%) of the 726 patients. These 58 were 21% of the total of 271 patients who were proven to have axillary metastasis in the end. Of the patients with ultrasonographically suspicious lymph nodes and negative cytology, 31% had tumor-positive sentinel nodes. Patients with preoperatively established metastases by ultrasonography and fine-needle aspiration cytology had more tumor-positive lymph nodes (P < .001) than patients with metastases established later on.ConclusionsThe sensitivity of ultrasonography and fine-needle aspiration cytology is 21%, and unnecessary sentinel node biopsy is avoided in 8% of the patients. This approach improves the selection of patients eligible for sentinel node biopsy.

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.

Automatic on-line inspection of patient setup in radiation therapy using digital portal images.

A new method is presented for inspection of patient setup in radiation therapy by automatic comparison of the patient position relative to the beam position in portal and simulator images. Quantification of patient-setup errors in terms of translation, rotation, and magnification is achieved by chamfer matching, a robust technique to match drawings and images, which is applied to both anatomy outlines and field edges. Applied to field edges, chamfer matching detects and visualizes deviations in field shape. Applied to anatomy outlines, the matching procedure quantifies and visualizes deviations in patient position relative to the radiation field. To test the method and to judge its feasibility, its behavior for four hundred different patient-setup deviations, which were simulated in four clinical images, was examined. These images show a top view of the pelvic region. The performance was measured in terms of accuracy and success rate for numerous cost functions and distance codings associated with the chamfer matching procedure. An average accuracy of 1.8 mm was found, a success rate of 90%, and an average overall computation time of 3 s on a 486 microcomputer. The whole analysis procedure is fast enough to allow on-line application.

Breast tomosynthesis in clinical practice: initial results

The purpose of this study was to assess the potential value of tomosynthesis in women with an abnormal screening mammogram or with clinical symptoms. Mammography and tomosynthesis investigations of 513 woman with an abnormal screening mammogram or with clinical symptoms were prospectively classified according to the ACR BI-RADS criteria. Sensitivity and specificity of both techniques for the detection of cancer were calculated. In 112 newly detected cancers, tomosynthesis and mammography were each false-negative in 8 cases (7%). In the false-negative mammography cases, the tumor was detected with ultrasound (n = 4), MRI (n = 2), by recall after breast tomosynthesis interpretation (n = 1), and after prophylactic mastectomy (n = 1). Combining the results of mammography and tomosynthesis detected 109 cancers. Therefore in three patients, both mammography and tomosynthesis missed the carcinoma. The sensitivity of both techniques for the detection of breast cancer was 92.9%, and the specificity of mammography and tomosynthesis was 86.1 and 84.4%, respectively. Tomosynthesis can be used as an additional technique to mammography in patients referred with an abnormal screening mammogram or with clinical symptoms. Additional lesions detected by tomosynthesis, however, are also likely to be detected by other techniques used in the clinical work-up of these patients.

3-D portal image analysis in clinical practice: an evaluation of 2-D and 3-D analysis techniques as applied to 30 prostate cancer patients

PURPOSE To investigate the clinical importance and feasibility of a 3-D portal image analysis method in comparison with a standard 2-D portal image analysis method for pelvic irradiation techniques. METHODS AND MATERIALS In this study, images of 30 patients who were treated for prostate cancer were used. A total of 837 imaged fields were analyzed by a single technologist, using automatic 2-D and 3-D techniques independently. Standard deviations (SDs) of the random, systematic, and overall variations, and the overall mean were calculated for the resulting data sets (2-D and 3-D), in the three principal directions (left-right [L-R], cranial-caudal [C-C], anterior-posterior [A-P]). The 3-D analysis included rotations as well. For the translational differences between the three data sets, the overall SD and overall mean were computed. The influence of out-of-plane rotations on the 2-D registration accuracy was determined by analyzing the difference between the 2-D and 3-D translation data as function of rotations. To assess the reliability of the 2-D and 3-D methods, the number of times the automatic match was manually adjusted was counted. Finally, an estimate of the workload was made. RESULTS The SDs of the random and systematic components of the rotations around the three orthogonal axes were 1. 1 (L-R), 0.6 (C-C), 0.5 (A-P) and 0.9 (L-R), 0.6 (C-C), 0.8 (A-P) degrees, respectively. The overall mean rotation around the L-R axis was 0.7 degrees, which deviated significantly from zero. Translational setup errors were comparable for 2-D and 3-D analysis (ranging from 1.4 to 2.2 mm SD and from 1.5 to 2.5 mm SD, respectively). The variation of the difference between the 2-D and 3-D translation data increased from 1.1 mm (SD) for zero rotations to 2.7 mm (SD) for out-of-plane rotations of 3 degrees, due to a reduced 2-D registration accuracy for large rotations. The number of times the analysis was not considered acceptable and was manually adjusted was 44% for the 2-D analysis, and 6% for the 3-D analysis. CONCLUSION True 3-D analysis of setup errors for a group of 30 patients with prostate cancer demonstrated that setup rotations are rather small. The deformation of the projected anatomy in portal images caused by out-of-plane rotations leads to a reduced 2-D registration accuracy. For rotations larger than 3 degrees this effect can be quite pronounced, making 3-D registration the preferred method. Furthermore, the automatic 3-D registration has a higher success rate, most likely because this technique uses more information compared to the 2-D method.

Radiation field edge detection in portal images

In fractionated radiation therapy with high energy photon beams, patient set-up is verified by analysing the position of the radiation field relative to the patient anatomy. This analysis is performed in an X-ray film, which has been exposed at the beam exit side of the patient during irradiation. Electronic portal image detectors, such as fluorescent screens, scanning diode arrays, or matrix ionization chambers produce an image within a few seconds, and enable an instantaneous verification of the patient set-up for every treatment session. An approach to detect radiation field edges in portal images using global threshold segmentation and local gradient information is presented.

Detection of extra-axillary lymph node involvement with FDG PET/CT in patients with stage II-III breast cancer.

PURPOSE The aim of this prospective study was to assess the incidence of extra-axillary lymph node involvement on baseline FDG PET/CT in patients with stage II-III breast cancer scheduled for neo-adjuvant chemotherapy. METHODS Patients with invasive breast cancer of >3 cm and/or proven axillary lymph node metastasis were included for before neo-adjuvant chemotherapy. Baseline ultrasound of the infra- and supraclavicular regions was performed with fine-needle biopsy as needed. Subsequently FDG PET/CT was performed. All visually FDG-positive nodes were regarded as metastatic based on the previously reported high specificity of the technique. RESULTS Sixty patients were included. In 17 patients (28%) extra-axillary lymph nodes were detected by FDG PET/CT, localised in an intra-mammary node (1 lymph node in 1 patient), mediastinal (2 lymph nodes in 2 patients), internal mammary chain (9 lymph nodes in 8 patients), intra- and interpectoral (6 lymph nodes in 4 patients), infraclavicular (5 lymph nodes in 4 patients) and in the contralateral axilla (3 lymph nodes in 2 patients). Ultrasound-guided cytology had detected extra-axillary lymph node involvement in seven of these patients, but was unable to detect extra-axillary nodes in the other 10 patients with positive extra-axillary lymph nodes on FDG PET/CT. Radiotherapy treatment was altered in 7 patients with extra-axillary involvement (12% of the total group). CONCLUSIONS FDG PET/CT detected extra-axillary lymph node involvement in almost one-third of the patients with stage II-III breast cancer, including regions not evaluable with ultrasound. FDG PET/CT may be useful as an additional imaging tool to assess extra-axillary lymph node metastasis, with an impact on the adjuvant radiotherapy management.

Interactive three dimensional inspection of patient setup in radiation therapy using digital portal images and computed tomography data

PURPOSE Presently, the majority of clinical tools to quantify deviations in patient setup during external beam radiotherapy is based on two-dimensional (2D) analysis of portal images. The purpose of this study is to develop a tool for the inspection of the patient setup in three dimensions (3D) and to validate its clinical advantage over methods based on 2D analysis in the presence of out-of-plane rotations. METHODS AND MATERIALS We developed an interactive procedure to quantify the setup deviation of the patient in 3D. The procedure is based on fast computation of digitally reconstructed radiographs (DRRs) in two beam directions and comparison of these DRRs with corresponding portal images. The potential of the tool is demonstrated on three selected cases of prostate and parotid gland treatment where conventional 2D analysis produced inconsistent results. The measurements from 3D analysis are compared with those obtained from the 2D analysis. RESULTS Despite application of an immobilization cast, two investigated parotid gland setups showed rotational deviations in 3D up to 3 degrees. Two-dimensional analysis of these deviations produced inconsistent results. Analysis of the selected prostate setup in 3D showed a rotational deviation of 7 degrees around the left-right axis, possibly causing displacement of the seminal vesicles toward the borders of the conformal boost fields. Using 2D analysis, this out-of-plane rotation was misinterpreted as a translation resulting in the failure to trigger the decision protocol to correct the setup after the first fraction. Using the 3D patient setup analysis procedure, an accuracy of the order of 1 mm and 1 degree (SD) could be obtained. The computation time of the interactive DRRs is of the order of 1 s on a 60 MHz PC. The complete interactive 3D analysis requires about 10 min. CONCLUSIONS Quantification of the patient setup in 3D provides essential additional information in cases where conventional 2D analysis is inconsistent, e.g., in the presence of out-of-plane rotations or geometrical degeneracies. The speed and accuracy of the interactive 3D patient setup inspection are acceptable for use in offline clinical studies and analysis of problem cases.

Optimization of automatic portal image analysis

The purpose of this study is to quantify and optimize the performance of an automatic portal image analysis procedure under clinical conditions and to compare the performance with that of human operators. A new method, based on analysis of variance, is introduced to quantify the clinical performance of portal image analysis tools in terms of systematic and random variations. The automatic portal image analysis procedure is based on chamfer matching. Two image enhancement techniques have been investigated in the automatic procedure: morphological top-hat (MTH) transformation and multiscale medial axis (MMA) transformation. The performance of these enhancements was quantified and optimized as a function of filter size using images obtained from clinical treatment. All images used for this study were obtained from pelvic treatment fields by means of an electronic portal imaging device. The random variations in the alignment of AP fields are typically 0.5 mm and 0.5 degrees (1 SD) for both the human operators and the optimized automatic analysis procedure. Random variations in the alignment of lateral pelvic fields are typically twice as large for all operators. MMA enhancement yields smaller random variations than MTH enhancement for lateral fields, but the differences are marginal for AP fields. The optimized automatic analysis procedure has a success rate ranging from 99% for AP large fields to 96% for lateral fields and 85% for AP boost fields. The accuracy of the method is comparable with the accuracy of the human operators for most investigated fields. For lateral boost fields and simultaneous boost fields, the random variations of the automatic analysis are typically two times larger than the variations of the human operators. Automatic analysis is 4 to 20 times faster than human operators yielding a large reduction in work load.