Björn Stenkvist

PREDICTING BREAST CANCER RECURRENCE

The prognostic value of 435 cytochemical, cytometrical, morphological, epidemiological, and clinical variables was analyzed in a prospective study of 179 breast cancer patients followed for five years after mastectomy. A variable reduction was obtained by first selecting variables correlated with recurrence rate in direct (Students t test) or correlation analysis with consideration of the type of variable analyzed (nominal, interval, ordinal). The 20 variables most strongly correlated with recurrence were analyzed by logistic stepwise regression analysis in order to find out what combination of variables had most discriminatory power in predicting recurrence. It was found that axillary metastization as such was correlated with a combination of variables describing mitotic frequency, size of primary tumor and differentiation of the primary tumor (average cluster size in fine‐needle biopsies). It was also found that there was a strong time dependency in the predictive power of the variables, so that different variable combinations predicted the recurrence rate during the first 2.5 year period (size of axillary metastases and primary tumor, number of lymphocytes around the tumor, mitotic frequency, and degree of differentiation) compared with the second 2.5 year period (variance of DNA content among tumor cell nuclei, number of lymphocytes around the tumor, occurrence of multiple tumors in the operated breast and occurrence of breast cancer among relatives). While other factors previously shown to be correlated with risk of recurrence were also found to be positively correlated here, they were neither as highly predictive as, nor did they increase the predictive value of the above mentioned combined variables. The current study strongly emphasizes that, at the present time, studies of recurrence prediction in human breast cancer should be based on an optimal combination of a number of variables which, independently, influence the prognosis. Further, the current study indicates that prerequisite methods for predicting breast cancer recurrence exist today.

Prognostic value of erb-B2 and myc amplification in breast cancer imprints

Background. Amplification of erb‐B2 and myc shows prognostic value in patients with operable breast cancer. Amplification is usually detected in tumor samples remaining after pathologic work‐up, preventing the examination of small tumors.

COMPUTER ANALYSIS OF CERVICAL CELLS AUTOMATIC FEATURE EXTRACTION AND CLASSIFICATION

A prescreening instrument for cervical smears using computerized image processing and pattern recognition techniques requires that single cells in the specimen can be automatically isolated and analyzed. This paper describes a dual wavelength method for automatic isolation of the cytoplasm and nuclei of cells. Density-oriented, shape-oriented and texture-oriented parameters were calculated and evaluated for more than 600 cells. It is shown that the computer can be taught to distinguish between normal and atypical cells with an accuracy of ca. 97%, while human classification reproducibility is ca. 95%. In addition, an attempt to assign a measure of atypia to individual cells is described.

Reproductive history and risk of breast cancer. A case‐control study in an unselected swedish populations

Variables in reproductive histories were studied in 179 consecutively detected, unselected breast cancer patients and age‐matched controls selected from a computerized population register. The comparison between patients and controls showed no significant difference in age at menarche, age at first birth, age at menopause or number of children. A subdivision into pre‐ and postmenopausal women yielded no further information. These results are at variance with most earlier reports, possibly because the controls here were selected from the whole female population instead of hospitalized patients. Our data do not support the view that it is possible to define groups at high risk for breast cancer on the basis of reproductive histories.

Higher frequency of gene amplification in breast cancer patients who received adjuvant chemotherapy

Amplification of certain genes is involved in resistance to chemotherapy. The development of such amplification in patients by drug treatment has not yet been established. We have assessed the appearance of gene amplification in breast cancer patients with recurrent disease. One group of patients had previously received adjuvant chemotherapy (cyclophosphamide, methotrexate, 5‐fluorouracil [CMF]) after surgery. The second group had not. All of these patients had developed recurrent disease and were receiving first‐line endocrine treatment (tamoxifen).

Detection and temporal appearance of multiple copies of c-erb-B2 genes in advanced mammary carcinoma using fine needle biopsies and the polymerase chain reaction

Aspiration of tumor cells by the fine-needle biopsy method yields only a small number of cells, which hampers conventional molecular analysis for the presence of multiple copies of oncogenes. We have therefore adopted the polymerase chain reaction (PCR) method to study semi-quantitatively the level of the c-erb-B2 gene in human breast tumor samples. Of 39 patients with mammary carcinoma, 7 (19%) contained multiple copies of c-erb-B2 genes, whereas only two samples failed to give informative data. Next the temporal appearance of multiple gene copies was examined in 20 patients with clinical stage IV disease. Tumor samples were obtained every second to third month from the same tumor lesion of each patient. None of the initial samples from each patient contained multiple copies of c-erb-B2. Of 16 patients that showed progressive clinical disease, 5 developed multiple gene copies, showing that the event occurs in clinical stage IV disease.

Multifocal breast carcinoma

The present study comprises 173 breast cancers in women living in Sweden. Mastectomy was performed and the surgical specimens were thoroughly scrutinized histopathologically with special attention given to the mammary tissue outside the dominant mass. Fifty-two patients (30 percent) had multifocal growth in the same breast as the dominant breast cancer. The patients have been followed up for 3 years after operation and compared with age-matched controls. The multifocal growth was not correlated with age, size of the tumor or death of the patient within 3 years. A previous diagnosis of benign breast disease was significantly more common among the cancer patients than among the controls, although it was unrelated to multifocal growth. This study stresses the importance of considering the high incidence of multifocal growth of breast cancer when discussing treatment by operation less radical than mastectomy.

High resolution segmentation of cervical cells.

A major problem in the automation of cervical cytology screening is the segmentation of cell images. This paper presents the present status of the work on that problem at the University of Uppsala. A dual resolution system is used. Suspect malignant cells are located at 4 mu resolution. Each such cell is rescanned at 0.5 mu resolution at two different wavelengths, 530 and 570 nm. The nucleus and the cytoplasm are isolated each by two independent methods. For the nucleus adaptive thresholding in the histogram of the 570 nm image and a contouring in a radially transformed version of that image is used. For the cytoplasm a two dimensional thresholding in the 2D histogram and a contouring in a radially transformed version of the 530 nm image is used. If the two nuclear masks agree the surrounding area is checked for disturbing objects. If also the cytoplasm masks agree and are without disturbing objects the whole cell is accepted. The result of the cytoplasm masks agree and are without disturbing objects the whole cell is accepted. The result of the segmentation is thus three categories; free cells, free nuclei and rejected objects. The shape of the objects belonging to the former two categories is checked and irregularly shaped ones are rejected as probably consisting of several overlapping nuclei. Cells passing also this test are classified as normal or malignant. The experience from using this algorithm is discussed and areas for further research are pointed out.

Breast cancer: prognostic significance of c-erb-B2 and int-2 amplification compared with DNA ploidy, S-phase fraction, and conventional clinicopathological features

SummaryThe prognostic value of oncogene amplification and conventional clinicopathological features was determined in consecutive breast cancers detected during 5 months in 1975–1976 in 4 Swedish counties. Material was collected from 162 of the 179 patients and tumor size, nodal status, FSH, estrogen/progesterone receptor status, DNA ploidy and S-phase fraction determined. Tissues remaining from 80 patients were stored frozen until 1991, when amplification of the oncogenes c-erb-B2 and int-2 was determined. We show that c-erb-B2 amplification (but not int-2 amplification) and positive axillary nodal status show prognostic significance for both survival and relapse-free survival in univariate and multivariate analysis. The other examined factors showed no significance.

Segmentation of cervical cells: Detection of overlapping cell nuclei☆

Abstract A method for detecting overlapping cell nuclei in Pap-stained cervical smears is described. The algorithm uses information both from the nuclear contour and from the density profile of the nucleus. For the analysis of the nuclear contour the smoothed difference chain code is used. From this code any significant concavities along the contour are found and a number of features describing their size and relative location are computed. If these clearly indicate an overlap situation the object is classified as an overlap. Otherwise a density profile is generated along a line orthogonal to the line joining the two major concavities. This profile is checked for peaks and valleys indicative of an overlap situation and a new set of features are generated and used to classify the object as single or overlapping. The algorithm performed reasonably well when tested on an independent test set of about 240 cell images.