Bartels Ph

Significance probability mapping: An aid in the topographic analysis of brain electrical activity

We illustrate the application of significance probability mapping (SPM) to the analysis of topographic maps of spectral analyzed EEG and visual evoked potential (VEP) activity from patients with brain tumors, boys with dyslexia, and control subjects. When the VEP topographic plots of tumor patients were displayed as number of standard deviations from a reference mean, more subjects were correctly identified than by inspection of the underlying raw data. When topographic plots of EEG alpha activity obtained while listening to speech or music were compared by t statistic to plots of resting alpha activity, regions of cortex presumably activated by speech or music were delineated. DIfferent regions were defined in dyslexic boys and controls. We propose that SPM will prove valuable in the regional localization of normal and abnormal functions in other clinical situations.

Long-term effects of an organophosphate upon the human electroencephalogram.

Abstract The brain electrical activity of workers exposed to the organophosphate compound (OP), sarin, was compared to that of control subjects. Exposed workers had a history of one or more documented accidental exposures to toxic levels of sarin. However, no exposed subject had exposure within 1 year of his examination. The comparison included standard clinical electroencephalograms (EEGs), computer-derived EEG spectral analysis, and standard overnight sleep EEGs. It was not possible to diagnose subjects individually by expert visual inspection of their EEGs. However, statistically significant between-group differences for both the visually inspected and computer-derived data were reported by both univariate and multivariate statistical methods. Different EEG changes revealed by visual inspection and computer-derived spectral analysis appear to reflect the differing sensitivites of these two analytic techniques. Statistically significant group differences included increased beta activity, increased delta and theta slowing, decreased alpha activity, and increased amounts of rapid eye movement sleep in the exposed population. It is suggested that the above findings represent an unexpected persistence of known short-term OP actions. It is also suggested that these results, when taken along with the reported long-term behavioral effects of OP exposure, provide parallel evidence that OP exposure can produce long-term changes in brain function.

An automated machine vision system for the histological grading of cervical intraepithelial neoplasia (CIN)

The histological grading of cervical intraepithelial neoplasia (CIN) remains subjective, resulting in inter‐ and intra‐observer variation and poor reproducibility in the grading of cervical lesions. This study has attempted to develop an objective grading system using automated machine vision. The architectural features of cervical squamous epithelium are quantitatively analysed using a combination of computerized digital image processing and Delaunay triangulation analysis; 230 images digitally captured from cases previously classified by a gynaecological pathologist included normal cervical squamous epithelium (n=30), koilocytosis (n=46), CIN 1 (n=52), CIN 2 (n=56), and CIN 3 (n=46). Intra‐ and inter‐observer variation had kappa values of 0.502 and 0.415, respectively. A machine vision system was developed in KS400 macro programming language to segment and mark the centres of all nuclei within the epithelium. By object‐oriented analysis of image components, the positional information of nuclei was used to construct a Delaunay triangulation mesh. Each mesh was analysed to compute triangle dimensions including the mean triangle area, the mean triangle edge length, and the number of triangles per unit area, giving an individual quantitative profile of measurements for each case. Discriminant analysis of the geometric data revealed the significant discriminatory variables from which a classification score was derived. The scoring system distinguished between normal and CIN 3 in 98.7% of cases and between koilocytosis and CIN 1 in 76.5% of cases, but only 62.3% of the CIN cases were classified into the correct group, with the CIN 2 group showing the highest rate of misclassification. Graphical plots of triangulation data demonstrated the continuum of morphological change from normal squamous epithelium to the highest grade of CIN, with overlapping of the groups originally defined by the pathologists. This study shows that automated location of nuclei in cervical biopsies using computerized image analysis is possible. Analysis of positional information enables quantitative evaluation of architectural features in CIN using Delaunay triangulation meshes, which is effective in the objective classification of CIN. This demonstrates the future potential of automated machine vision systems in diagnostic histopathology. Copyright

Automated location of dysplastic fields in colorectal histology using image texture analysis

Automation in histopathology is an attractive concept and recent advances in the application of computerized expert systems and machine vision have made automated image analysis of histological images possible. Systems capable of complete automation not only require the ability to segment tissue features and grade histological abnormalities, but must also be capable of locating diagnostically useful areas from within complex histological scenes. This is the first stage of the diagnostic process. The object of this study was to develop criteria for the automatic identification of focal areas of colorectal dysplasia from a background of histologically normal tissue. Fields of view representing normal colorectal mucosa (n=120) and dysplastic mucosa (n=120) were digitally captured and subjected to image texture analysis. Two features were selected as being the most important in the discrimination of normal and adenomatous colorectal mucosa. The first was a feature of the co‐occurrence matrix and the second was the number of low optical density pixels in the image. A linear classification rule defined using these two features was capable of correctly classifying 86 per cent of a series of training images into their correct groups. In addition, large histological scenes were digitally captured, split into their component images, analysed according to texture, and classified as normal or abnormal using the previously defined classification rule. Maps of the histological scenes were constructed and in most cases, dysplastic colorectal mucosa was correctly identified on the basis of image texture: 83 per cent of test images were correctly classified. This study demonstrates that abnormalities in low‐power tissue morphology can be identified using quantitative image analysis. The identification of diagnostically useful fields advances the potential of automated systems in histopathology: these regions could than be scrutinized at high power using knowledge‐guided image segmentation for disease grading. Systems of this kind have the potential to provide objectivity, unbiased sampling, and valuable diagnostic decision support.

Analysis of the capillary architecture in the precursors of prostate cancer : Recent findings and new concepts

OBJECTIVE To report on recent findings and new concepts in the remodeling of the capillary architecture in the precursors of prostate cancer. METHODS Immunohistochemical methods have been adopted in prostate cancer and in its precursors (prostatic intra-epithelial neoplasia) to investigate capillary pattern changes-which were mainly analyzed as capillary frequency- and the degree of endothelial cell proliferation. Several features related to the capillary architecture have been considered. Manual, semiautomatic, and automatic (machine vision) types of evaluation have been used to quantify the features. RESULTS The data available indicate that: (1) Going from normal prostate through prostatic intra-epithelial neoplasia up to invasive adenocarcinoma, an increasing proportion of capillaries becomes shorter, with open lumen and undulated external contour and with greater proliferation of the endothelial cells and greater expression of type IV collagenase. The highest proportion of touching capillaries is seen in normal prostate, while the lowest is found in invasive adenocarcinoma, being intermediate in prostatic intra-epithelial neoplasia. (2) When total androgen ablation is induced, there is no proliferation of the endothelium, whereas the capillaries are reduced in frequency and represented by small vessels lined by flat endothelial cells and with an open lumen. (3) Automation in the evaluation of the capillary architecture is feasible with a machine vision system. CONCLUSIONS The progression in prostate carcinogenesis is associated with changes in the capillary architecture. There are some preliminary data indicating that total androgen ablation can inhibit the angiogenesis in precursors of prostate cancer.

Unrestricted principal components analysis of brain electrical activity: Issues of data dimensionality, artifact, and utility

SummaryPrincipal components analysis (PCA) was performed on the 1536 spectral and 2944 evoked potential (EP) variables generated by neurophysiologic paradigms including flash VER, click AER, and eyes open and closed spectral EEG from 202 healthy subjects aged 30 to 80. In each case data dimensionality of 1500 to 3000 was substantially reduced using PCA by magnitudes of 20 to over 200. Just 20 PCA factors accounted for 70% to 85% of the variance. Visual inspection of the topographic distribution of factor loading scores revealed complex loadings across multiple data dimensions (time-space and frequency-space). Forty-two non-artifactual factors were successful in classifying age, gender, and a separate group of 60 demented patients by linear discriminant analysis. Discrimination of age and gender primarily involved EP derived factors, whereas dementia primarily involved EEG derived factors. Thirty-eight artifactual factors were identified which, alone, could not discriminate age but were relatively successful in discriminating gender and dementia. The need to parsimoniously develop real neurophysiologic measures and to objectively exclude artifact are discussed. Unrestricted PCA is suggested as a step in this direction.

Prostate cancer prevention: review of target populations, pathological biomarkers, and chemopreventive agents.

Chemoprevention is the administration of agents to prevent induction of cancer, or to inhibit or delay its progression. In prostatic neoplasia, the time from tumour initiation and progression to invasive carcinoma often begins in men in the fourth and fifth decades of life and extends across decades. This phenomenon represents a unique opportunity to arrest or reverse the process of carcinogenesis with the use of chemopreventive agents. For prostate cancer, as for other cancer targets, development of successful chemopreventive strategies requires suitable cohorts, reliable biomarkers for evaluating chemopreventive eYcacy, and well characterised agents. Histopathologists have an important role in prostate chemoprevention. They define the high risk groups, recognise the surrogate end markers, and evaluate the morphological eVects of the agents on the prostate tissue specimens.

Safety and Efficacy of Dose-Intensive Oral Vitamin A in Subjects with Sun-Damaged Skin

Purpose: Previously, we reported the results of a Phase III, placebo-controlled trial in 2,297 randomized participants with moderately severe actinic keratoses wherein 25,000 IU/day vitamin A caused a 32% risk reduction in squamous cell skin cancers. We hypothesized that dose escalation of vitamin A to 50,000 or 75,000 IU/day would be both safe and more efficacious in skin cancer chemoprevention. Experimental Design: One hundred and twenty-nine participants with severely sun-damaged skin on their lateral forearms were randomized to receive placebo or 25,000, 50,000, or 75,000 IU/day vitamin A for 12 months. The primary study end points were the clinical and laboratory safety of vitamin A, and the secondary end points included quantitative, karyometric image analysis and assessment of retinoid and rexinoid receptors in sun-damaged skin. Results: There were no significant differences in expected clinical and laboratory toxicities between the groups of participants randomized to placebo, 25,000 IU/day, 50,000 IU/day, and 75,000 IU/day. Karyometric features were computed from the basal cell layer of skin biopsies, and a total of 22,600 nuclei from 113 participants were examined, showing statistically significant, dose-response effects for vitamin A at the 25,000 and 50,000 IU/day doses. These karyometric changes correlated with increases in retinoic acid receptor α, retinoic acid receptor β, and retinoid X receptor α at the 50,000 IU/day vitamin A dose. Conclusions: The vitamin A doses of 50,000 and 75,000 IU/day for 1 year proved safe and equally more efficacious than the 25,000 IU/day dose and can be recommended for future skin cancer chemoprevention studies.

A Phase 2a Study of Topical Perillyl Alcohol Cream for Chemoprevention of Skin Cancer

The chemopreventive and antitumor properties of perillyl alcohol (POH) that were studied preclinically indicate that topical POH inhibits both UVB-induced murine skin carcinogenesis (squamous cell tumor models) and 7,12-dimethylbenz(a)anthracene–induced murine melanoma (transgenic models involving tyrosinase-driven Ras). A previous phase 1 clinical trial in participants with normal-appearing skin showed that topical POH cream was well tolerated at a dose of 0.76% (w/w). Here, we performed a 3-month, double-blind, randomized, placebo-controlled phase 2a trial of two different doses of topical POH in individuals with sun-damaged skin. Participants applied POH cream twice daily to each dorsal forearm. Baseline and end-of-study biopsies were taken from each participant to evaluate whether the topical application of POH was effective in reversing actinic damage as evidenced by normalization of quantitative skin histopathologic scores and change in nuclear chromatin pattern as measured by karyometric analysis. There was a borderline reduction in the histopathologic score of the lower-dose POH group compared with the placebo (P = 0.1), but this was not observed in the high-dose group. However, in the high-dose group, a statistically significant reduction in the proportion of nuclei deviating from normal was observed by the use of karyometric analysis (P < 0.01). There was no statistical significance shown in the lower-dose group. No changes were observed in p53 expression, cellular proliferation (by proliferating cell nuclear antigen expression), or apoptosis in either treatment group compared with the placebo group. These results suggest that whereas our karyometric analyses can detect a modest effect of POH in sun-damaged skin, improved delivery into the epidermis may be necessary. Cancer Prev Res; 3(2); 160–9

An evaluation of intelligent prognostic systems for colorectal cancer.

In this paper we describe attempts at building a robust model for predicting the length of survival of patients with colorectal cancer. The aim of the research, reported in this paper, is to study the effective utilisation of artificial intelligence techniques in the medical domain. We suggest that an important research objective of proponents of intelligent prognostic systems must be to evaluate the additionality that AI techniques can bring to an already well-established field of medical prognosis. Towards this end, we compare a number of different AI techniques that lend themselves to the task of predicting survival in colorectal cancer patients. We describe the pros and cons of each of these methods using the usual metrics of accuracy and perspicuity. We then present the notion of intelligent hybrid systems and evaluate the role that they may potentially play in developing robust prognostic models. In particular we evaluate a hybrid system that utilises the k Nearest Neighbour technique in conjunction with Genetic Algorithms. We describe a number of innovations used within this hybrid paradigm used to build the prognostic model. We discuss the issue of censored patients and how this issue can be tackled within the various models used. In keeping with our objective of studying the additionality that AI techniques bring to building prognostic models, we use Coxs regression as a standard and compare each AI technique with it, attempting to discover their capabilities in enhancing prognostic methods in medicine. In doing so we address two main questions--which model fits the data best?, and are the results obtained by the various AI techniques significantly different from those of Coxs regression? We conclude this paper by discussing future enhancements to the work presented and lessons learned from the study to date.