Propagation of registration uncertainty during multi-fraction cervical cancer brachytherapy.

Multi-fraction cervical cancer brachytherapy is a form of image-guided radiotherapy that heavily relies on 3D imaging during treatment planning, delivery, and quality control. In this context, deformable image registration can increase the accuracy of dosimetric evaluations, provided that one can account for the uncertainties associated with the registration process. To enable such capability, we propose a mathematical framework that first estimates the registration uncertainty and subsequently propagates the effects of the computed uncertainties from the registration stage through to the visualizations, organ segmentations, and dosimetric evaluations. To ensure the practicality of our proposed framework in real world image-guided radiotherapy contexts, we implemented our technique via a computationally efficient and generalizable algorithm that is compatible with existing deformable image registration software. In our clinical context of fractionated cervical cancer brachytherapy, we perform a retrospective analysis on 37 patients and present evidence that our proposed methodology for computing and propagating registration uncertainties may be beneficial during therapy planning and quality control. Specifically, we quantify and visualize the influence of registration uncertainty on dosimetric analysis during the computation of the total accumulated radiation dose on the bladder wall. We further show how registration uncertainty may be leveraged into enhanced visualizations that depict the quality of the registration and highlight potential deviations from the treatment plan prior to the delivery of radiation treatment. Finally, we show that we can improve the transfer of delineated volumetric organ segmentation labels from one fraction to the next by encoding the computed registration uncertainties into the segmentation labels.

Prostate brachytherapy postimplant dosimetry: automatic plan reconstruction of stranded implants.

PURPOSE: Plan reconstruction for permanent implant prostate brachytherapy is the process of determining the correspondence between planned and implanted seeds in postimplant analysis. Plan reconstruction informs many areas of brachytherapy quality assurance, including the verification of seed segmentation, misplacement and migration assessment, implant simulations, and the dosimetry of mixed-activity or mixed-species implants. METHODS: An algorithm has been developed for stranded implants which uses the interseed spacing constraints imposed by the suture to improve the accuracy of reconstruction. Seventy randomly selected clinical cases with a mean of 23.6 (range 18-30) needles and mean density of 2.0 (range 1.6-2.6) 2.0 (range 1.6-2.6) seeds/cm3 were automatically reconstructed and the accuracy compared to manual reconstructions performed using a custom 3D graphical interface. RESULTS: Using the automatic algorithm, the mean accuracy of the assignment relative to manual reconstruction was found to be 97.7 +/- 0.5%. Fifty-two of the 70 cases (74%) were error-free; of seeds in the remaining cases, 96.7 +/- 0.3% were found to be attributed to the correct strand and 97.0 +/-0.3% were correctly connected to their neighbors. Any necessary manual correction using the interface is usually straightforward. For the clinical data set tested, neither the number of seeds or needles, average density, nor the presence of clusters was found to have an effect on reconstruction accuracy using this method. CONCLUSIONS: Routine plan reconstruction of stranded implants can be performed with a high degree of accuracy to support postimplant dosimetry and quality analyses.

Population-based study of biochemical and survival outcomes after permanent 125I brachytherapy for low- and intermediate-risk prostate cancer.

OBJECTIVES: To analyze the biochemical and survival outcomes after permanent low-dose-rate prostate brachytherapy in a large, consecutive, population-based cohort of patients. METHODS: A total of 1006 consecutive implants were performed from July 20, 1998 to October 23, 2003 for men with low-risk and "low-tier" intermediate-risk prostate cancer. The prescribed minimal peripheral dose was 144 Gy, using 0.33 mCi (125)I sources and a preplan technique with a strong posterior-peripheral dose bias. Most patients (65%) had received 6 months of androgen deprivation therapy. Supplemental external beam radiotherapy was not used. The prognostic features, dose metrics, and follow-up data were prospectively collected. Kaplan-Meier and Cox regression analyses were used to assess the factors associated with freedom from biochemical recurrence and survival. RESULTS: The median patient age at treatment was 66 years. The median follow-up was 54 months for biochemical outcomes and 66 months for survival. The actuarial freedom from biochemical recurrence rate was 95.6% +/- 1.6% at 5 years and 94.0% +/- 2.2% at 7 years. On multivariate analysis, the pretreatment prostate-specific antigen level (P = .03) and androgen deprivation therapy use (P = .04) were predictive of the freedom from biochemical recurrence. The actuarial rates of distant metastasis and disease-specific death at 5 years were both <1%. The overall survival rate at 5 years was 95.2% +/- 1.4% and was 93.4% +/- 1.8% at 7 years. On multivariate analysis, only age was predictive of overall survival (P = .011). CONCLUSIONS: When consistently planned and delivered, low-dose-rate brachytherapy, without supplemental external beam radiotherapy or intraoperative planning, can produce cancer-specific outcomes for men with low- and "low-tier" intermediate-risk prostate cancer at least equal to that produced by dose-escalated external beam radiotherapy or surgical prostatectomy.

3T3 cell motility and morphology before, during, and after exposure to extremely-low-frequency magnetic fields.

Automated image cytometry techniques were used to measure motility and morphology in 3T3 fibroblasts exposed to extremely-low-frequency (ELF) magnetic fields. Cell motility and morphology were measured as a function of time before, during, and after 3-4 hour exposures to vertically oriented, 100 microTRMS sinusoidal magnetic fields at various frequencies in the 10-63 Hz range. Sham exposures were also carried out. No static DC fields were applied, but the geomagnetic field was almost vertical and, therefore, had a large component (28.3 microT) parallel to the applied AC field. The morphology and motile behavior of the cells were characterized by mathematically defined descriptors, which were calculated and averaged for the exposure period as well as for control periods that preceded and followed the exposure period. Each experiment involved the tracking of 100 cells that were subjected to one of the test frequencies (unless a sham exposure was being conducted). Statistical analysis of the results showed that even small changes of 10-20% could be significant at the P < .05 level. Changes on this order were measured in a significant proportion of the experiments. However, because such results were seen for both the sham-exposed and the ELF-exposed cells, and because the range of values that was obtained for the sham exposures was the same as that obtained for the ELF exposures, we concluded that there was no evidence to show that any of the measured changes were attributable to the applied ELF magnetic field.

Can colony size be used to detect low-dose effects?

Many insults at low doses are defined as nontoxic, even though obvious effects do occur. Among these are changes in colony size when clonogenic survival is assessed. Early attempts to quantify radiation effects on colony size have been reported, but the time-consuming nature of these experiments did not encourage the use of this parameter as an end point. Recently, however, developments in image cytometry technology have provided alternative, less labor-intensive means of measuring colony size. These techniques have been used in our ongoing investigations of radiation effects at low doses. Data accumulated to date show a measurable dose dependence of colony size in clones classed as survivors. This dose dependence is characterized by fluctuations in the 0-1.5-Gy dose range, followed by a gradual decrease in colony size at higher doses. The fluctuations at low doses correspond qualitatively to the concavity, thought to be indicative of inducible repair phenomena, that has been observed in cell survival curves in the same dose range. This concavity was also seen in the current study, but its detection appeared to be dependent on the method used to score survivors.

Cell survival measurements at low doses using an automated image cytometry device.

The statistical precision of cell survival data measured at low doses can be greatly improved if the number of cells assayed at each dose point is known exactly. This paper describes an image cytometry technique that has been developed for this purpose. Treated cells are plated into tissue culture flasks, and after attachment their locations are determined with 98% accuracy by automated scanning procedures. These locations are revisited after an appropriate incubation period to assay for colony formation. Colonies may be scored either manually or using image data collected by the device. Additional information, such as heterogeneity of colony size, can also be obtained.

The relative biological effectiveness of 60Co gamma-rays, 55 kVp X-rays, 250 kVp X-rays, and 11 MeV electrons at low doses.

The relative biological effectiveness (RBE) of selected low-LET radiation modalities (55 kVp X-rays, 250 kVp X-rays, 60Co gamma-rays, and 11 MeV electrons) was investigated for survival of two cell lines (V79 and CHO). Detailed measurements were made in the low (0 to 3 Gy) dose range using an image cytometry device to accurately determine the number of cells assayed at each dose point. Data were also collected in the high dose range (0 to 10 Gy) using conventional counting and plating techniques. RBE values (+/- 1 SE) varied from 1.0 +/- 0.07 (V79 cells) and 1.2 +/- 0.05 (CHO cells) at high doses to 1.3 +/- 0.07 (V79) and 1.4 +/- 0.1 (CHO) at low doses for 55 kVp X-rays, from 1.1 +/- 0.05 (V79) and 1.1 +/- 0.04 (CHO) at high doses to 1.1 +/- 0.06 (V79) and 1.2 +/- 0.2 (CHO) at low doses for 250 kVp X-rays, and from 1.1 +/- 0.08 (V79) and 1.0 +/- 0.04 (CHO) at high doses to 1.0 +/- 0.06 (V79) and 0.9 +/- 0.1 (CHO) at low doses for 11 MeV electrons. Only the low and high dose RBEs for 55 kVp X-rays relative to 60Co gamma-rays were significantly different.

Computer automation in measurement and analysis of cell motility in vitro.

The application of computerized techniques to the study of cell motility has allowed direct examination and quantitation of individual cell movement and morphology. This has stimulated interest in theoretical models of cell motility, and has prompted the need for increasingly sophisticated approaches to analyze and present cell motility data. In this article we review some of the microscope systems currently used to study cell motility, and give more details on such a system developed in our own laboratory, the DMIPS Cell Analyzer. Brief examples of its application to the field of cell motility are provided. Some areas of further research in the field of automated microscopy are also discussed.

Effect of focus on cell detection and recognition by the Cell Analyzer.

The effect of defocusing on the quality of signals from live cells detected by an automated image cytometry device, the Cell Analyzer, was examined. The influence of these effects on the ability of this device to automatically locate cells plated into a tissue culture flask was then determined by measuring the performance of cell detection and recognition procedures as a function of focus setting. Acceptable limits for deviation from the optimal focus setting (as determined by microscope objective position) were found to be similar for both these procedures, ranging from 40 microns below to 25 microns above the optimal focus position. These limits were asymmetrical about ideal focus due to a pronounced asymmetry in the effects of positive and negative defocusing on the cell signal.

Automated detection and recognition of live cells in tissue culture using image cytometry.

An automated image cytometry device, the Cell Analyzer, was used to locate live V79 cells plated at low densities in a tissue culture flask. Cells and other objects were detected by moving the flask in steps across a linear solid-state image sensor. The step size was selected to be small enough to allow detection of all the cells in the area being scanned but sufficiently large so that most cells would be detected on only one image line. To distinguish cells from other detected objects, a recognition algorithm utilizing 18 characteristic cell signal features was developed. The algorithm first tests whether a set of feature values falls within specified upper and lower bounds, and then applies a linear discriminant function to the remaining data to further discriminate cells from debris. False-positive errors of 5% or less were achieved with this method, whereas 15-35% of cells were misclassified as debris.