Prognostic role of serum thymidine kinase 1 kinetics during neoadjuvant chemotherapy for early breast cancer.

BACKGROUND: Emerging data support the use of thymidine kinase 1 (TK1) activity as a prognostic marker and for monitoring of response in breast cancer (BC). The long-term prognostic value of TK1 kinetics during neoadjuvant chemotherapy is unclear, which this study aimed to elucidate. METHODS: Material from patients enrolled to the single-arm prospective PROMIX trial of neoadjuvant epirubicin, docetaxel and bevacizumab for early BC was used. Ki67 in baseline biopsies was assessed both centrally and by automated digital imaging analysis. TK1 activity was measured from blood samples obtained at baseline and following two cycles of chemotherapy. The associations of TK1 and its kinetics as well as Ki67 with event-free survival and overall survival (OS) were evaluated using multivariable Cox regression models. RESULTS: Central Ki67 counting had excellent correlation with the results of digital image analysis (r = 0.814), but not with the diagnostic samples (r = 0.234), while it was independently prognostic for worse OS [adjusted hazard ratio (HRadj) = 2.72, 95% confidence interval (CI) 1.19-6.21, P = 0.02]. Greater increase in TK1 activity after two cycles of chemotherapy resulted in improved event-free survival (HRadj = 0.50, 95% CI 0.26-0.97, P = 0.04) and OS (HRadj = 0.46, 95% CI 0.95, P = 0.04). There was significant interaction between the prognostic value of TK1 kinetics and Ki67 (pinteraction 0.04). CONCLUSION: Serial measurement of serum TK1 activity during neoadjuvant chemotherapy provides long-term prognostic information in BC patients. The ease of obtaining serial samples for TK1 assessment motivates further evaluation in larger studies.

Neutral effect of ultra-low-dose continuous combined estradiol and norethisterone acetate on mammographic breast density.

OBJECTIVE: To compare the effects of two different ultra-low doses of continuous combined hormone therapy and placebo on mammographic breast density in postmenopausal women. METHODS: A subpopulation of 255 postmenopausal women from the CHOICE trial were randomly assigned to 0.5 mg 17beta-estradiol (E2) + 0.25 mg norethisterone acetate (NETA), 0.5 mg E2 + 0.1 mg NETA, or placebo. Women using hormone replacement therapy (HRT) up to 2 months prior to the study were excluded; 154 women fulfilled the inclusion criteria. Mammograms were performed at baseline and after 6 months. Breast density was evaluated by visual classification scales and a computer-assisted digitized technique. RESULTS: No significant differences were detected between the active treatment groups and the placebo group in the digitized quantification. The mean baseline values for density around 20% were unchanged after 6 months. Also, visual classifications showed no increase in breast density in any study group. CONCLUSION: In contrast to currently available bleed-free regimens, the new ultra-low-dose combination of 0.5 mg E2 and 0.1 mg NETA seems to have very little or even a neutral effect on the breast. Both digitized quantification and visual assessment of breast density were unchanged after 6 months. Larger prospective studies should be performed to confirm this new finding.

Testosterone addition during menopausal hormone therapy: effects on mammographic breast density.

OBJECTIVE: To study the effect on mammographic breast density of testosterone addition during combined estrogen/progestogen therapy in postmenopausal women. METHODS: A prospective, randomized, double-blind, placebo-controlled trial. A total of 99 women were given 2 mg 17beta-estradiol and 1 mg norethisterone acetate in combination with either a testosterone patch (300 mug/24 h) or a placebo patch. Mammographic breast density at baseline and after 6 months was assessed by visual classification scales and by digitized quantification. A standardized questionnaire was used to quantify subjective breast symptoms. RESULTS: Visual classifications showed an increase in mammographic density in 18-30% of the women, with no significant differences between the treatment groups. The mean increase of the area of dense breast during treatment according to digitized assessment was 7.4% in the placebo group and 5.4% in the testosterone group. Breast symptoms showed a positive association with the increase in density (r(s) = 0.34; p < 0.01). Symptoms were most pronounced at 2 months of treatment. Density, both at baseline (r(s) = -0.35; p < 0.01) and change during treatment (r(s) = -0.28; p < 0.01) showed a negative association with free testosterone levels. CONCLUSION: The addition of testosterone does not appear to influence mammographic breast density in women concurrently treated with a common oral estrogen/progestogen regimen for a period of 6 months.

Expression of Syndecan-1 in histologically normal breast tissue from postmenopausal women with breast cancer according to mammographic density.

OBJECTIVE: To analyze the expression of Syndecan-1 in dense and non-dense human breast tissue. METHODS: Specimens of histologically normal tissue were obtained from postmenopausal women undergoing surgery for breast cancer. Each tissue block was subject to radiological examination and pair-wise samples of dense and non-dense tissue were collected. Semi-quantitative assessment of immunohistochemical staining intensity for Syndecan-1 and estrogen receptor subtypes was performed. RESULTS: The expression of Syndecan-1 in all tissue compartments was significantly higher in dense than in non-dense specimens. The strongest staining was recorded in stromal tissue. There was a strong correlation between epithelial estrogen receptor alpha and stromal cell Syndecan-1 expression in dense tissue (rs = 0.7; p = 0.02). This association was absent in non-dense tissue. CONCLUSION: An increase of Syndecan-1 in all tissue compartments and a redistribution from epithelium to stroma may be a characteristic feature for dense breast tissue.

Ultrasound-guided large needle core biopsy of the axilla.

PURPOSE: To study the diagnostic yield and safety aspects of large needle core biopsy of pathologic lesions in the axillary region using a semi-automatic biopsy gun. MATERIAL AND METHODS: A series of 21 consecutive large needle core (14G, 2.1 mm) biopsies of the axilla was evaluated. The biopsies were performed under ultrasound guidance with one (n = 13) or two (n = 8) needle passes. The results were correlated to the clinical, mammographic, ultrasound and surgical histopathologic findings. RESULTS: In 18 patients, specimens large enough for diagnosis were retrieved. In two patients the specimens were insufficient and non-diagnostic. In one patient with a non-malignant yield the result was false-negative. No neural or vascular injury occurred. CONCLUSION: The procedure might be safely employed in the diagnosis of ultrasonographically demonstrable lesions of the axilla, whenever specimens larger than those obtainable with a fine needle are desired.

Semiautomatic core biopsy. A modified biopsy technique in breast diseases.

PURPOSE: To evaluate a semiautomatic gun to retrieve diagnostic core specimens of lesions in the breast and the axillary region. MATERIAL AND METHODS: In a series of 180 consecutive core biopsies (2.1 mm), 145 (142 breasts and 3 axillae) were performed with a semiautomatic gun (18 stereotaxic and 127 US-guided) from lesions presenting mammographically as microcalcifications (n = 15) and opacities (n = 130). The gun did not work satisfactorily in 34 lesions, which were tumors with a very hard consistency. One additional patient was excluded because of technical failure. Biopsy diagnoses in the 145 patients were correlated to surgical histopathology, follow-up mammograms and/or clinical findings. RESULTS: Histologic examination of the specimens resulted in correct diagnoses in 89% (129/145) of the total material and in 87% (108/124) of cancers. In 107 cases, in which only 1 specimen was obtained, 83 of 89 cancers (87%) were detected. Length of specimens ranged from 3 mm (n = 2) to 17 mm (n = 31). Among patients with a 17-mm-long specimen, there was only 1 false-negative diagnosis. CONCLUSION: The semiautomatic gun provided diagnostic specimens in a majority of cases and could be used as an alternative to the automatic guns when size or location of the lesions necessitates a high precision. It was not suitable for use in very hard tumors.

Behaviour of the 2.1-mm (14 G) automated biopsy needle in phantoms.

PURPOSE: To study the behaviour of the 2.1-mm (14 G) core biopsy needle in targets of different consistencies and to correlate the needle behaviour to lengths of the samples. MATERIAL AND METHODS: A series of butter blocks at temperatures of -5 degrees C, -2 degrees C, +1 degrees C, +4 degrees C, +7 degrees C, +10 degrees C, +13 degrees C, +16 degrees C and +19 degrees C simulating lesions of different hardness in human breast, were passed with needles (3 passes at each temperature). Inner needle behaviour was studied both with and without outer cannula effect. RESULTS: At +4 degrees C to +13 degrees C the needle had a curved course, deviated to the side of its tip. At +4 degrees C, the needle was most deviated (range 4, 8, 10 degrees ) and the samples were largest (8, 12, 12 mm). At -5 degrees C to +1 degrees C the needle was bent, the cannula was not triggered and no sample was obtained. At +16 degrees C and +19 degrees C the needle had a straight course and the length of the sample was decreasing. CONCLUSION: Behaviour of the inner needle as well as the cannula depends on the hardness of the target. Targets of intermediate hardness yield adequate samples when the inner needle takes a curved course deviated toward the tip and get restored by the cannula.

Effect on sensitivity and specificity of mammography screening with or without comparison of old mammograms.

PURPOSE: To evaluate the effect of old mammograms on the specificity and sensitivity of radiologists in mammography screening. MATERIAL AND METHODS: One hundred and fifty sets of screening mammograms were examined by 3 experienced screeners twice: once without and once in comparison with older mammograms. The films came from a population-based screening done during the first half of 1994 and comprised all 35 cancers detected during screening in 1994, 12/24 interval cancers, 14/34 cancers detected in the following screening and 89 normal mammograms. RESULTS: Without old mammograms, the screeners detected an average of 40.3 cancers (range 37-42), with a specificity of 87% (85-88%). With old mammograms, the screeners detected 37.7 cancers (range 34-42) with a specificity of 96% (94-99%). The change in detection rate was not significant. However, the increase in specificity was significant for each screener (p = 0.0002-0.03). CONCLUSION: Mammography screening with old mammograms available for comparison decreased the false-positive recall rate. The effect on sensitivity, however, was unclear.

Nipple discharge disorders: current diagnostic management and the role of fiber-ductoscopy.

Nipple discharge disorders is a field in which there has been both increasing awareness on the part of patients and advances in management. Today secretion from nipples can be classified according to its color, cellularity and biology. To be significant a discharge should be true, spontaneous, persistent and non-lactational. Moreover there are methods to differentiate patients who require surgical intervention from those who do not. Surgically significant nipple discharges are watery, serous (yellow), serosanguineous and bloody. Cytology smears of discharge material have helped to classify the cellular material, providing information about normality, atypia and malignancy and also about papillary formation of the exfoliated cells. Tests such as Hemoccult help to discover occult blood in the secreted fluid. Modern immunological tests can be performed on cytology smears where occurrence of high levels of carcinoembryonic antigen could indicate a latent malignancy. Galactography investigation is today the state-of-the-art approach to investigate patients with nipple discharge disorders and this examination can demonstrate the size, location and extent of an intraductal abnormality. Modern high-resolution ultrasound techniques are helpful in visualizing intraductal disorders and are becoming a good complementary approach if not an alternative to traditional radiology techniques. Recently even MR galactography has been shown to be of diagnostic value, but not as informative as regular galactography. The most sophisticated investigation method, which can also be used therapeutically, is fiber-ductoscopy of the concerned duct in a breast. This technique, although expensive and in its infancy, is a fascinating and promising approach for inspecting the intraductal lumina. In this article the background, current investigation methods and possibilities of the technique are described, as well as the most sophisticated ways to deal with nipple discharge disorders in human breasts.

Imaging breasts with silicone implants.

Over the last two decades, the use of breast implants both for breast augmentation and for breast reconstruction following mastectomy has increased substantially. It is estimated that around two million women have undergone breast augmentation, while hundreds of thousands have had breast reconstruction surgery. Different types of material have been used for breast implants, but silicone gel implants have been the dominating implant type. Many implants can lead to complications, such as hardening and rupture, and may therefore need in vivo evaluation by imaging, particularly if they lead to clinical symptoms. They can also pose problems in the assessment of surrounding breast tissue by conventional mammography. In this respect, imaging modalities such as ultrasound, computed tomography and magnetic resonance imaging offer greater possibilities to assess a failing implant, as well as surrounding breast tissue. Several factors, mainly of a psychological nature, lead to requests for breast implants. In this review article, only the imaging aspects of breasts with silicone gel implants will be dealt with. Each modality is concisely presented with its possibilities and limitations.

Mammographic features, predictors of early ipsilateral breast tumour recurrences?

Mammograms from 69 patients with Stage I/II breast cancer, operated on using breast-conserving surgery between 1987-1990 were blindly re-evaluated in order to predict retrospectively ipsilateral breast tumour recurrences. The study cohort was divided into two groups of 34 and 35 patients. Each group was matched according to age, the time at risk and to presence or absence of an ipsilateral breast tumour recurrence. The mammographic reinterpretation was performed by two radiologists that correctly predicted an ipsilateral breast tumour recurrence in 81%. Mammographic characteristics, such as diffuse microcalcifications, multifocality, solitary densities, especially of stellate type near the nipple and/or spicula in the vicinity of the retroareolar region were more often associated with an ipsilateral breast tumour recurrence. Data from this limited series suggest that certain mammographic features seem to correlate with the ability of the tumour to recur locally. Hence, mammography can play a prognostic role in deciding the treatment of choice in operable breast cancer.

The general mammography screening program in Stockholm. Organisation and first-round results.

This presentation describes the organization and first-round results of the Stockholm mass mammography screening program, and discusses ways of checking the quality of an ongoing screening program. The Stockholm mammography screening program started in 1989 at five independent screening units, and comprises more than 150,000 women aged 50 to 69 years. The first round was completed in June 1991. Compliance during the studied period was 70.6%, and the recall rate was 3.0% of the attending women. Breast cancer was diagnosed in 676 women, of whom 90 (13.3%) had a cancer in situ. The cancer prevalence rate was thus 6.3 cancers per 1,000 screened women. Surgery was performed on 925 women, of whom 249 had benign lesions, giving a benign/malignant ratio of 0.37 to 1. Fifty-two per cent of the cancer patients were operated with breast conserving surgery. The median size of the invasive cancers was 12 mm; almost 80% were node-negative. Experience from the first two years of this mass mammography screening program shows that it meets the major quality requirements. One of the main future goals is to maintain the high quality of the program. Another important goal is a further increase in compliance.

Dietary habits and mammographic patterns in patients with breast cancer.

Between 1983 and 1986, dietary history interviews were conducted with 238 women aged 50-65 years who had surgery for stage I-II breast cancer. Diagnostic mammograms were coded in line with Wolfe's criteria in N1, P1, P2, and Dy patterns. Women with Dy pattern reported significantly higher intake of total fat, monounsaturated fatty acids (FA), polyunsaturated FA, n-3 FA, n-6 FA in per cent of energy (E%), and alpha-tocopherol in mg/10 MJ. Fat intake was lowest in women with N1 pattern and highest in those having Dy pattern. Patients having ER-rich cancers and Dy pattern reported significantly higher intake of total fat, monounsaturated FA, polyunsaturated FA, n-6 FA (E%), and alpha-tocopherol (mg/10 MJ), as well as significantly lower intake of carbohydrate (E%) and calcium (g/10 MJ). In the stepwise multivariate analysis, the multivariate-odds ratio (OR) for having P2 + Dy patterns was 1.06 (95% confidence interval (CI), 1.02-1.12) for each increment in E% of total fat. In women with ER-rich tumors this OR was 1.09 (95% CI, 1.02-1.16). The highest self-reported body mass index (BMI) was observed in women with N1 + P1 patterns. OR for having P2 + Dy patterns was 0.91 (95% CI, 0.83-0.98) for each increment in 1 kg/m2 of BMI. The results suggest that dietary habits affect the mammographic parenchymal pattern in women with breast cancer and that a high fat intake is associated with a higher proportion of mammograms with Dy pattern in such patients.

Radial scars detected mammographically in a breast cancer screening programme.

Radial scars are getting more and more common since the implementation of mammography as a diagnostic tool in screening women for breast cancer. At the Karolinska Hospital, 18,987 asymptomatic women, between the ages of 50 and 69, were screened for breast cancer by means of mammography during the period August 1989 to May 1991. A total of 735 (3.87%) women were recalled for additional views after initial mammograms and 463 (2.44%) were assessed with the help of cytology. In all 175 (0.92%) women were selected for surgery and 146 (0.77%) had histologically verified cancers. The remaining 29 (0.15%) had non-malignant lesions of which 11 (0.06%) were radial scars. All radial scars were diagnosed on mammograms and later confirmed with histology. The radiologic characteristics were found to be (a) rather thick and long radiating structures accompanied by radiolucent linear structures parallel to some of the spicules, (b) absence of calcifications, (c) radiolucent areas in the central body of the lesion, (d) an average mean size of 6 mm and (e) changing image in different views. Most of the lesions, 73% (8/11), were in moderately dense breasts and there was no specific relation to the right or left breast. A majority of radial scars, 64% (7/11), were found in the upper outer quadrants, 27% (3/11) in the lower outer quadrants and 9% (1/11) in the lower inner quadrant. Literature shows that histology uses many synonyms for radial scars and therefore team work between the radiologists and pathologists is suggested for better conformity of the diagnosis.

Expression of the c-erbB-2 proto-oncogene product and nuclear DNA content in benign and malignant human breast parenchyma.

The expression of the c-erbB-2 proto-oncogene product was investigated immunohistochemically in 474 formalin-fixed and paraffin-embedded human breast tissue samples. The series included 32 benign and 26 hyperplastic lesions, 32 carcinomas in situ and 384 invasive breast carcinomas, 107 of which were less than 1 cm in diameter. Cytometric DNA assessments were performed on histopathologically or cytodiagnostically identified cell nuclei, using image analysis. C-erbB-2 immunoreactivity was not seen in normal parenchyma or in benign and hyperplastic lesions. Mammary carcinomas in situ were more frequently immunoreactive (59%) than invasive neoplasms (23%). Invasive tumours more than 1 cm in diameter immunoreacted more often (26%) than small invasive carcinomas (16%). C-erbB-2 expression in regional lymph node metastases was the same as in the corresponding primary tumours. Significant differences were observed between the c-erbB-2 expression in DNA diploid and aneuploid lesions; for carcinomas in situ the figures were 40% and 72%, respectively. Invasive carcinomas of DNA diploid type rarely showed c-erb-B-2 expression, irrespective of tumour size and nodal status (7-11%). DNA aneuploid tumours were more frequently immunoreactive with increasing levels during progression (32-41%). Our data indicate that genetically stable invasive mammary tumours seem rarely to express the c-erbB-2 protein, even during progression, whereas genetically unstable invasive neoplasms frequently show c-erbB-2 immunoreactivity which increases during tumour progression.

Radiologic aspects of breast cancers detected through a breast cancer screening program.

Early detection of breast cancer and reduced mortality in women with this disease is today attributed to the widespread use of mammography. High-quality performance is essential in every step of breast cancer screening programs in order to avoid unnecessary anxiety and surgery in the women concerned. This report presents the radiologic aspects of screening cancers. A total of 8370 asymptomatic women aged between 50-69 years were screened with 2-view mammography, of which only 70 (0.84%) were selected for surgery after a thorough work-up. Cancers were verified histologically in 61 women and 9 showed non-malignant histology, giving a cancer detection rate of 7.3 cancers per thousand screened asymptomatic woman. The benign/malignant ratio in the operated cases is thus approximately 1:7. The cancers detected showed all existing types of mammographic features where 77% (47 cases) showed rather typical findings, such as spiculated densities both with and without microcalcifications and with microcalcifications only. The remaining 23% (14 cases) showed parenchymal distortions, asymmetric and well-defined densities, both with and without calcifications. Our results indicate that surgery can be minimized without impairing the breast cancer detection rate. Radiologists in screening programs should be aware that a large proportion of non-palpable breast cancers present in rather unconventional forms. This point is important in order to maintain a high cancer detection rate and thereby justify the widespread use of mammography as a screening tool for breast cancer in asymptomatic women.

Radiological evidence of response to electrochemical treatment of breast cancer.

A non-surgical therapeutic approach is illustrated with a case report of a breast cancer. Percutaneous implantation of electrodes in a breast permitted electrochemical treatment of a clinically, radiologically and cytologically verified cancer. Electrophoresis was induced between two implanted electrodes for about 2 h. No complaints were reported and no complications were observed. Bi-annual mammographic follow up could not disclose palpable or mammographic evidence of tumour remnants 2 years later.