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Biomedical subjects

P W Hamilton

Publications and source records attributed to P W Hamilton.

At least 19 recordsLinked to original sources
PubMed1998

Cell proliferation studies in primary synovial chondromatosis.

Primary synovial chondromatosis (PSC) is thought to be a cartilaginous metaplasia, but it may recur locally and malignant change has been reported. Histologically, the cartilage is usually cellular, with binucleate forms. These findings suggest that the disease is not simply a metaplasia but imply a proliferative component. In this study, immunohistochemical detection of Ki-67 protein using an antigen retrieval microwave heating technique and DNA image cytometry (VIDAS image analysis system) has been used to assess the proliferative activity in 20 cases of PSC and the results have been compared with those obtained in other cartilage tissues: ten enchondromas, ten chondrosarcomas, and ten samples of normal articular cartilage. There was no detectable staining for Ki-67 protein in cases of PSC or in benign tissues, but there was a significant association between Ki-67 labelling index and grade in the chondrosarcomas (P < 0.01). The absence of mitotic figures and the lack of Ki-67 protein in PSC are consistent with a metaplasia. All enchondromas gave diploid DNA histograms but non-diploid histograms were obtained i eight cases (40 per cent) of PSC, with significant populations of hyperdiploid and DNA aneuploid cells. The mean DNA content, the percentage of hyperdiploid cells, the percentage of DNA aneuploid cells, and the 2c deviation index were all significantly higher in PSC than in enchondromas (P < 0.01). These findings with image cytometry suggest a proliferative process in the development of at least some cases of PSC. In terms of cell proliferative activity, PSC appears to occupy a position which is intermediate between benign enchondromas and malignant chondrosarcomas, which may explain the aggressive clinical behaviour occasionally seen in this condition.

Bone Neoplasms↗
PubMed1998

Inter- and intra-observer variation in the histopathological reporting of cervical squamous intraepithelial lesions using a modified Bethesda grading system.

OBJECTIVE: 1. To assess inter- and intra-observer variation in the histopathological reporting of cervical colposcopic biopsies using a histologic modification of the cytological Bethesda grading system; 2. to determine the histologic profile of those cases which resulted in diagnostic disagreement. METHODS: Consecutive cervical colposcopic biopsies (n = 125) were assessed independently by six experienced histopathologists. Cases were classified as normal, low grade squamous intraepithelial lesion or high grade squamous intraepithelial lesion. Six months later the process was repeated. The degree of inter and intra-observer variation was assessed by kappa statistics. All cases in which there was less than perfect inter and intra-observer agreement were reviewed by the coordinator of the study. RESULTS: In the first round of the study inter-observer agreement was generally poor, with unweighted and weighted kappa values ranging from 0.15 to 0.58 (average 0.30) and from 0.21 to 0.61 (average 0.36) respectively. In the second round inter-observer agreement was better, with unweighted and weighted kappa values ranging from 0.08 to 0.55 (average 0.33) and from 0.22 to 0.59 (average 0.42). Ten of the 15 pairs of observers achieved fair inter-observer agreement using weighted kappa analysis. The degree of intra-observer agreement was better, unweighted and weighted kappa values ranging from 0.26 to 0.61 (average 0.47) and from 0.34 to 0.62 (average 0.51) respectively. Two of the six participants achieved fair intra-observer agreement and two achieved good intra-observer agreement using weighted kappa analysis. There were marked difficulties in the separation of normal squamous epithelium from low grade squamous intraepithelial lesion and in the separation of low grade from high grade squamous intraepithelial lesions. Histopathological review revealed that many of the difficulties in the separation of normal and low grade squamous intraepithelial lesion were in the distinction between superficial vacuolated cells and true koilocytes. Difficulties also resulted in the separation of basal cell hyperplasia, inflammatory associated changes and immature squamous metaplasia from low grade squamous intraepithelial lesion. Conditions which resulted in difficulty in the separation of low grade and high grade squamous intraepithelial lesions included florid koilocytotic change and immature metaplastic squamous epithelium with atypia. In some cases, there was a full spectrum of diagnoses from normal to high grade squamous intraepithelial lesion. These were largely cases of immature metaplastic squamous epithelium with atypia and of thin or atrophic squamous epithelium with atypia. CONCLUSIONS: Most pairs of observers can achieve fair inter-observer agreement in the reporting of cervical colposcopic biopsies using a modified Bethesda system. Intra-observer agreement is also generally fair to good using this system. It may be that a two tier grading system is more appropriate for the histopathological reporting of these biopsies than the traditional three-tier intraepithelial neoplasia (CIN) system.

Biopsy↗
PubMed1998

Machine vision in the detection of prostate lesions in histologic sections.

OBJECTIVE: To explore the utility of N-gram encoding for the automated detection and delineation of regions of histologic abnormality in tissue sections of prostate. STUDY DESIGN: Digitized imagery of tissue sections from normal prostate glandular tissue, stroma and regions of well- and poorly differentiated lesions was recorded and successively subdivided into square subregions of 256 x 256 to 16 x 16 pixels. N-grams of N = 2 to N = 6 were computed, with each element assuming a value representing an optical density interval 0.30 units wide, covering the range from optical density = 0.0 to 1.80. Then, from a large database, prototype frequency histograms of the different N-grams were established. For each subregion the Euclidean distances to the different prototype histograms were computed and defined as "distance to prototype" features. Standard discriminant analyses and a nonparametric classifier were used to assign subregions to the different tissue categories. RESULTS: Classification of subregions was achieved for most discrimination tasks at a correct recognition rate ranging from 85% to 100% on both training set and test set data, with a few exceptions. N-grams of N > 4 had considerable discriminatory power. CONCLUSION: N-gram encoding has the potential to provide highly discriminating, texture-based characterization of subregions of digitized imagery of prostate lesions and may be very useful in the development of decision procedures for the automated detection of prostate lesions by a machine vision system.

Algorithms↗
PubMed1998

Statistical histometry of the basal cell/secretory cell bilayer in prostatic intraepithelial neoplasia.

OBJECTIVE: To delineate the sampling requirements for a histometric assessment of progression in low grade and high grade prostatic intraepithelial neoplasia (PIN) lesions. STUDY DESIGN: Images of whole glands from normal prostates, low grade PIN lesions and high grade PIN lesions were digitized. The images were processed by a machine vision system and automatically segmented, and a number of histometric characteristics descriptive of the disruption of the basal cell layer were extracted. Next, high-resolution images of secretory cell nuclei still facing or no longer facing intact segments of the basal cell layer were recorded and karyometrically analyzed. RESULTS: For the characterization of an individual lesion a minimum of 20-30 glands should be analyzed to provide an estimate of a progression index. Then, a change in progression, or due to regression, of approximately 16% can be documented. The disruption of the basal cell layer is accompanied by statistically highly significant changes in the chromatin texture and spatial distribution in secretory cell nuclei no longer facing an intact segment of that layer. CONCLUSION: Automated histometry by machine vision can provide valuable quantitative data for diagnostic assessment and for monitoring the efficacy of chemopreventive treatment.

Analysis of Variance↗
PubMed1998

Nuclear chromatin texture in prostatic lesions. I. PIN and adenocarcinoma.

OBJECTIVE: To document changes in the chromatin pattern in secretory cell nuclei from prostates with prostatic intraepithelial neoplasia (PIN) or adenocarcinoma. STUDY DESIGN: High-resolution images of nuclei were recorded, and a set of features descriptive of the chromatin texture and spatial distribution was computed. From this data set, features undergoing a monotonic trend of progression were selected and plotted to reveal trends in lesion progression. RESULTS: The nuclear chromatin in secretory cells in prostates with either PIN or malignant adenocarcinoma undergoes distinct and statistically significant changes in its texture and spatial distribution. Two trends of progressive change were observed. First, the values of a number of features descriptive of the clumpiness of the chromatin increase from values found in normal prostates to those recorded for nuclei from low grade to high grade PIN lesions. The second trend is a decrease in the values of the same features from those found in nuclei from high grade PIN still facing an intact basal cell layer to those no longer facing such a layer. This may be the first detectable step in progression towards development of a malignant lesion. There is a further decrease in nuclei in glands immediately adjacent to adenocarcinoma and in malignant lesions themselves. CONCLUSION: The described changes may lend themselves to the monitoring of lesion progression or of response to treatment or to chemopreventive intervention.

Adenocarcinoma↗
PubMed1998

Nuclear chromatin texture in prostatic lesions. II. PIN and malignancy associated changes.

OBJECTIVE: The objective of this study was to identify and document prostatic intraepithelial neoplasia (PIN) and malignancy associated changes in secretory cell nuclei from visually normal appearing tissue regions of prostates harboring PIN or adenocarcinoma. STUDY DESIGN: High-resolution digitized images of nuclei were recorded in histologically normal appearing tissue regions at defined distances from the margin of PIN or malignant lesions. Features descriptive of nuclear chromatin texture were computed and used to derive a discriminant function score for each nucleus. RESULTS: Secretory cell nuclei in prostates harboring either PIN or adenocarcinoma were shown to have statistically significantly different chromatin texture from secretory cell nuclei recorded in prostates free from any such lesion. The expression of PIN or malignancy associated changes was documented for distances up to 10 mm from the margin of a lesion. CONCLUSION: The finding of characteristic changes in nuclear chromatin texture of nuclei from histologically normal appearing tissue in prostates with PIN or adenocarcinoma offers the potential for higher sensitivity of detection of such lesions and for earlier detection of changes potentially preceding the development of clinically significant disease.

Cell Nucleus↗
PubMed1998

Chromatin texture signatures in nuclei from prostate lesions.

OBJECTIVE: To characterize nuclei from prostatic lesions in a highly specific manner by developing a nuclear chromatin texture signature and to characterize lesions by means of their composition of nuclei with diverse degrees of deviation from normal. STUDY DESIGN: High-resolution digitized imagery of nuclei from normal prostates, from prostatic neoplastic lesions of low and high grade and from histologically normal appearing regions of prostates with low and high grade prostatic intraepithelial neoplasia (PIN) lesions were recorded. A set of 65 features descriptive of the spatial and statistical distribution of nuclear chromatin was computed for each nucleus. These features were arranged and processed to form a distinctive signature. A distance metric from "normal" was defined and computed for each nucleus. RESULTS: Profiles of feature values can, after suitable scaling, be presented as distinctive feature value signatures. For many practical applications, profiles based on a standardized distance from normal nuclei may be more useful. Such profiles allow the derivation of a progression curve, showing increasing distances for diagnostic groups with increasing lesion progression up to high grade PIN lesions. Within each diagnostic group different cases show distinctive distributions of nuclei with differing degrees of deviation from normal, allowing the derivation of a lesion signature. CONCLUSION: Nuclear chromatin texture signatures may be of value for the characterization of both nuclei and lesions. They are based on a more comprehensive use of information offered by the nuclear chromatin pattern than that included in classification methods. While these signatures offer a more specific characterization of a clinical sample, they also are subject to more variability within a diagnostic category. This may not be due to randomness but may reflect some actual differences between lesions.

Adenocarcinoma↗
PubMed1998

Case diagnosis as positive identification in prostatic neoplasia.

OBJECTIVE: To apply a distance measure and Bayesian belief network-based methodology to the positive identification of case diagnosis in prostatic neoplasia. STUDY DESIGN: Eight morphologic and cellular features were analyzed in 20 cases of normal prostate, 20 of low grade prostatic intraepithelial neoplasia (PIN), 20 of high grade PIN, 20 of prostatic adenocarcinoma with a cribriform pattern and 20 of prostatic adenocarcinoma with an acinar pattern. The diagnostic distance was evaluated to measure the "extent" to which the feature outcomes of the individual cases differed from the expected profile of outcomes in typical cases of normal prostate, low and high grade PIN, and cribriform and large acinar adenocarcinoma. Belief values were evaluated with a Bayesian belief network (BBN). RESULTS: A bivariate representation of the cumulative absolute diagnostic distances of all the cases from the prototypes of normal prostate and cribriform adenocarcinoma was made. Three separate groups of cases were observed, corresponding to normal prostate, low grade PIN and cribriform adenocarcinoma. An additional group was formed by the cases of high grade PIN and acinar adenocarcinoma--i.e., there was complete overlap between the diagnostic distance values of cases belonging to these two categories. However, these cases showed differences in clue outcomes. To explore the contribution of such observations to case identification, a bivariate representation of the diagnostic distances from high grade PIN and acinar adenocarcinoma was made. The cases then formed five separate groups corresponding to the five diagnostic categories. When the individual cases were considered, their shortest distance was from the prototype of the category into which they were originally diagnosed. The BBN gave these diagnostic categories the highest belief values. CONCLUSION: The combined evaluation of diagnostic distance and belief represents an identification procedure. The numeric value of certainty characterizes individual cases according to the level of progression from PIN toward cancer.

Bayes Theorem↗
PubMed1998

Automated histometry in quantitative prostate pathology.

OBJECTIVE: To review progress on the development of machine vision and image understanding in prostate tissue histology and to discuss the problems and opportunities afforded to pathology through the use of these techniques. STUDY DESIGN: A variety of concepts in machine vision are explored, and methodologies are described that have been developed to deal with the complexities of histologic imagery. The theory of human vision and its impact on machine vision are discussed. Software has been specifically developed for the analysis of prostate histology, allowing accurate gland segmentation, basal cell identification and measurement of vascularization within lesions. RESULTS: Image interpretation can be achieved using knowledge-based image analysis and the application of local object-oriented processing. This successfully allows an automated quantitative analysis of histologic morphology in the diagnosis of prostate intraepithelial neoplasia and invasive prostatic cancer. The use of low-power image scanning, based on textural or n-gram mapping, permits the development of fully automated devices for the rapid detection of tissue abnormalities. High-power, knowledge-guided scene segmentation can be carried out for the quantitative analysis of cellular features and the objective grading of the lesion. CONCLUSION: Automated tissue section scanning and image interpretation is now possible and holds much promise in prostate pathology and other diagnostically demanding areas. Issues of standardization still need to be addressed, but the development of such systems will undoubtedly enhance our diagnostic capabilities through the automation of time-consuming procedures and the quantitative evaluation of disease processes.

Humans↗
PubMed1997

Computerized scene segmentation for the discrimination of architectural features in ductal proliferative lesions of the breast.

The distinction between ductal hyperplasia (DH) and ductal carcinoma in situ (DCIS) still remains a problem in the histological diagnosis of non-invasive breast lesions. In this study, a method was developed for the automatic segmentation and quantitative analysis of breast ducts using knowledge-guided machine vision. This permitted duct profiles and intraduct lumina to be identified and their shape, size, and number computed. These were used to derive measures of duct cribriformity and architectural complexity which were examined as an objective tool in the characterization of duct pattern in proliferative lesions. A total of 215 images of ducts were digitally captured from 22 cases of DCIS and 21 cases of DH diagnosed independently by two pathologists. The cribriformity index proved to be a useful measure of duct architecture, showing a nosotonic increase with increasing duct complexity. The number of lumins also increased with increasing overgrowth of ductal epithelium until the duct was filled. Discriminant analysis of the duct characteristics for benign and malignant groups selected the lumen area/duct area ratio and the duct area as significant discriminatory variables and they were combined into a discriminant function. Of the lumens features, the mean area of the lumen and the polar average (mean of the distribution of the number of events with an increasing spiral from the centre of the duct) were combined into a second discriminant function. Plotting cases against these two functions provided good separation of DH and DCIS groups, with correct classification estimated on the training sample as being over 80 per cent. With an increasing incidence of complex proliferative lesions arising from mammography, the ability to diagnose these lesions correctly is more important than ever. The use of expert system-guided machine vision facilitates the quantitative evaluation of breast duct architecture; along with established histological and cytological criteria, it is hoped that this will lead to a more objective means of diagnosis and disease classification.

Aged↗
PubMed1997

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.

Adenomatous Polyps↗
PubMed1997

Quantitative study of ductal breast cancer--patient targeted prognosis: an exploration of case base reasoning.

Current analytic methodologies allow the extraction, even from small tumor masses, of extensive information on the biologic characteristics of malignant lesions, such as tumor aggressivity, metastatic potential, drug resistance, and host interactions. Clinical practice now offers a wide range of therapeutic strategies. Information technological advances offer the opportunity to refer to very large data bases of patient anamnestic data, response to treatment and clinical outcome. There is a need to formulate therapy and prognosis for each individual case. Case based reasoning is a knowledge based methodology where the outcome for complex situations can be predicted by referring to a large data base of cases of known outcomes. The preliminary data obtained from this study suggest that case based reasoning may offer a promising approach to individual targeted prognosis.

Breast Neoplasms↗
PubMed1997

Validation of a rapid method to quantify apoptosis in superficial bladder cancer.

OBJECTIVES: To derive and validate a rapid method for calculating apoptotic indices in superficial transitional cell carcinoma (TCC) as a measure of chemosensitivity to mitomycin. MATERIALS AND METHODS: Apoptotic cells, identified by light microscopy in 20 superficial TCC specimens, were expressed as an index of the total tumour cell population within defined fields. For a given field, the total cell population was estimated by: (i) an exhaustive count of the total number of cells in the field and (ii) an abbreviated method in which the number of cells in a subfield was multiplied to provide an estimate of the total field number. Field and specimen estimates were compared using agreement statistics and the intra- and inter-observer reproducibility of apoptotic indices calculated. RESULTS: Cellularity and apoptotic indices obtained using method (ii) were correlated significantly with the true cell counts (P < 0.001). Agreement statistics showed that only 9.4% of counts fell outside two standard deviations (SD) from the mean in field analysis, and only 10% of counts fell outside 2 SD from the mean in specimen analysis. There was a fivefold variation in tumour cell counts among individual fields. CONCLUSIONS: The reported variation in cellularity among fields shows that the calculation of apoptosis must use the total cell population as the reference. The limits of agreement for the estimated and true cell counts are small enough to be confident that the shorter method to estimate cellularity can be used in place of counting all cells.

Antibiotics, Antineoplastic↗
PubMed1997

Diagnostic distance of high grade prostatic intraepithelial neoplasia from normal prostate and adenocarcinoma.

OBJECTIVE: To develop a distance measure based methodology to support the morphological evaluation of high grade prostatic intraepithelial neoplasia (PIN), a direct precursor of prostate cancer. METHODS: Eight morphological and cellular features were analysed in 20 cases of high grade PIN found in radical prostatectomy specimens from patients with adenocarcinoma. The diagnostic distance was evaluated to measure the extent to which the feature outcomes of the individual high grade PIN cases differed from the expected outcome profile of normal prostate, low and high grade PIN, and cribriform and large acinar adenocarcinoma. The belief value for high grade PIN was evaluated with a Bayesian belief network (BBN). RESULTS: Complete separation existed between the cumulative absolute diagnostic distances of these 20 cases from the prototype feature outcomes of high grade PIN and normal prostate the values for which were < or = 3 (range 0 to 3) and > or = 9 (range 9 to 15), respectively. The distances from low grade PIN (range 3 to 9), cribriform adenocarcinoma (range 2 to 8), and large acinar adenocarcinoma (range 5 to 10) were intermediate and showed overlap in their distribution. When taking into consideration whether the severity of feature changes was increasing or decreasing in comparison with the category prototype outcomes, the cumulative directional diagnostic distances from high grade PIN ranged from -3 to +3. Positive distance values were seen relative to low grade PIN (range +3 to +9) and relative to normal prostate (range +9 to +15). Negative values were found relative to cribriform adenocarcinoma (range -8 to +2). The distance values from large acinar adenocarcinoma ranged from -2 to +4 and partly overlapped with those from the high grade PIN category. A bivariate scattergram derived from both diagnostic distance measures showed excellent separation between the groups' distances. BBN analysis confirmed the morphology based diagnosis. The distance evaluation resulted in 18 cases whose belief value for high grade PIN ranged from 0.60 to 0.87. In the remaining two cases the results of the BBN analysis showed a belief value of 0.50 and 0.57 for low grade PIN and of 0.49 and 0.38 for high grade PIN, respectively. CONCLUSIONS: Distance measure based methodology represents a useful diagnostic decision support tool for the accurate evaluation of high grade PIN.

Adenocarcinoma↗
PubMed1997

DNA denaturation sensitivity may invalidate bromodeoxyuridine--DNA flow cytometric analysis of potential doubling times in colorectal tumours.

BACKGROUND: Flow cytometric analysis of 5-bromo-2'-deoxyuridine (BrdU)-substituted DNA has been used to calculate tumour cell proliferation rate. In this methodology, DNA denaturation, commonly by hydrochloric acid, is essential to expose incorporated BrdU for quantification with monoclonal antibodies. This study was designed to establish the validity of this technique by examining the change in flow cytometric DNA profiles introduced by DNA denaturation procedures. METHODS: Four experiments were performed using suspensions of nuclei derived from human colorectal tumours exposed in vivo to 150 mg/m2 BrdU 8-11 h before sampling. RESULTS: After denaturation with hydrochloric acid 2 mol/l a significant decrease was observed in the DNA aneuploid G1 population (P < 0.001) with a concurrent increase in the DNA aneuploid S phase fraction (P < 0.05). These changes were independent of the washing-centrifugation step and were maximal at different hydrochloric acid concentrations for different tumours. CONCLUSION: Hydrochloric acid denaturation introduces a tumour-specific non-linear variation in the analysis of BrdU.

Aged↗
PubMed1996

p53 mutation, allele loss on chromosome 17p, and DNA content in ovarian carcinoma.

The aim of this investigation was to explore the relationships between p53 mutation, DNA aneuploidy, 17p deletions, and clinical stage in ovarian cancer. Nuclear suspensions were obtained by tissue disaggregation, stained with propidium iodide, and analysed on a Coulter EPICS Elite flow cytometer. DNA cell cycle analysis was performed using Multicycle software (Phoenix Flow Systems). DNA extracted from paraffin-embedded archival carcinomas/non-tumour tissue was used as template for PCR amplification of the microsatellite dinucleotide repeat polymorphism D17S513, a locus telomeric to p53 on 17p13.1. Allele loss at D17S513 was detected in 64.5 per cent of carcinomas (20 of 31 informative cases). DNA aneuploidy was detected in 20 of 54 (37 per cent) carcinomas. Eight of ten cases previously shown to harbour p53 mutations showed aneuploid DNA content. Although ten other DNA aneuploid cases had shown no p53 mutations, the results show a statistically significant association between p53 mutation and DNA aneuploidy (P < 0.01). Furthermore, the mean DNA index of the DNA aneuploid cases was significantly higher in p53 mutant cases compared with those showing no p53 mutation (P = 0.02). There was also a significant association between p53 mutations and stage, between ploidy and stage, and between allelic deletions at D17S513 or p53 and stage, but not between these allelic deletions and ploidy. p53 mutations appear to be associated with DNA aneuploidy in ovarian cancer independently of 17p deletions. p53 mutations, DNA aneuploidy, and 17p deletions are associated with late stage.

Alleles↗