Michael Medl

Real-time spatial compound imaging in breast ultrasound

To determine the role of real-time spatial compound imaging in breast ultrasound (US), 38 patients with a total of 50 benign changes (fibroadenomas, cysts, lactiferous duct dilatation) underwent both conventional B-mode US and real-time spatial compound imaging under standardized examination settings. Subsequently, images were reviewed independently by three readers experienced in breast US and evaluated according to a multistage scoring system with regard to the presence of artefacts, delineation of boundaries and depiction of internal structures. With significant reader concordance, real-time spatial compound imaging was found to produce speckle reduction with improvement of tissue differentiation, increased conspicuity of low-contrast lesions, enhanced delineation of capsular margins and ducts, and improved depiction of internal architecture of solid lesions, as well as clearer visualization of cystic contents due to clutter reduction. Preservation of central acoustic enhancement and lateral edge shadowing in cysts and fibroadenomas, however, was recorded better in conventional imaging.

Preoperative CA 125: An independent prognostic factor in patients with stage I epithelial ovarian cancer

Objective To evaluate the prognostic importance of preoperative CA 125 levels in patients with International Federation of Gynecology and Obstetrics (FIGO) stage I epithelial ovarian cancer in comparison with the established prognostic factors: degree of differentiation, FIGO substage, and age. Methods In a retrospective analysis, the traditional prognostic factors and CA 125 levels (cutoff value 65 U/mL) were studied in 201 patients who were treated in five centers during 1984–1993. Patients with borderline tumors or nonepithelial ovarian carcinomas were excluded, as were women in whom CA 125 had not been determined preoperatively. Results In univariate analysis (Mantel test), overall survival decreased significantly in patients positive for CA 125 (P < .001). Substage (P = .004) and histologic grade (P = .01) also significantly influenced survival prognosis. When the effects of preoperative CA 125 levels were correlated with histologic grade, all three subgroups with CA 125 levels equal to or greater than 65 U/mL were associated with a decreased survival probability (grade 1, P = .04; grade 2, P = .003; grade 3, P = .01). Multivariate analysis (Cox model) identified preoperative CA 125 as the most powerful prognostic factor for survival (P < .001), the risk of dying of disease being 6.37 times higher (95% confidence interval 2.39–16.97) in CA 125-positive patients. Although FIGO substage retained its significant influence on survival (P = .03), histologic grade and age were not prognostically important. Conclusion Randomized trials investigating the efficacy of adjuvant treatment in patients with FIGO stage I epithelial ovarian cancer should also include stratification by preoperative CA 125 levels.

Color-coded and spectral Doppler flow in breast carcinomas--relationship with the tumor microvasculature.

The phenomenon of tumor angiogenesis is an important aspect of understanding tumor biology. Studies in breast carcinoma have shown microvessel density (MVD) assessed by immunohistochemistry to be of prognostic importance in primary breast cancer. On the other hand, recently developed highly sensitive color-coded Doppler techniques offer a noninvasive method to examine neovascularisation in breast tumors. The purpose of this study was to determine the relationship between Doppler flow parameters and microvessel count assessed by immunohistochemistry. Fifty-three patients with primary breast cancer were examined preoperatively with color-coded Doppler ultrasound. The obtained Doppler frequency spectra were analyzed for peak systolic flow velocity (Vmax). Following surgery, paraffin-embedded microsections were immunohistochemically stained for factor VIII-related antigen. Tumor angiogenesis was assessed by microvessel count under light microscopy. Undifferentiated tumors correlated with high MVD (p=0.009) whereas other clinicopathological parameters were not associated with MVD. Color Doppler signals were detected in 50 out of 53 breast tumors. Evaluation of tumor flow velocity with various clinicopathological parameters showed a significant correlation with tumor size (p=0.0001) and lymph node metastasis (p=0.02). However, there was no significant correlation between MVD and intratumoral blood flow velocity assessed by color-coded Doppler. Our findings showed that Doppler flow measurement did not correlate with the extent of tumor angiogenesis of breast cancer. The present data give circumstantial evidence that microvessel count assessed by immunohistochemistry reflects the microvascular network, whereas tumor vasculature documented by Doppler ultrasound supplies information on the macrovasculature.

The use of colour-coded and spectral Doppler ultrasound in the differentiation of benign and malignant breast lesions

The aim of this study was to evaluate the role of colour-coded and spectral Doppler sonography to predict the benign or malignant nature of breast lesions. A total of 112 women with mammographically suspicious breast lesions were investigated prior to surgery. Thirty-nine breast carcinomas and 73 benign lesions were evaluated for the resistance index, pulsatility index and the flow velocity. A resistance index of > or = 0.70 was characteristic of malignant tumours with a sensitivity of 82% and a specificity of 81%. The positive predictive value was 70% and the negative predictive value 89%. Doppler sonography offers one possible method for further investigation of patients with mammographic abnormalities.

Relevance of sonographic B-mode criteria and computer-aided ultrasonic tissue characterization in differential/diagnosis of solid breast masses

We aimed to evaluate the differential diagnostic value of a method of computer-assisted texture analysis in comparison to established ultrasonographic B-mode characteristics in the examination of solid breast masses. At two centers, 77 patients presenting with a solid mass on B-mode scan were studied at 7.5 MHz. Description of B-mode appearance included assessment of tumor shape, borders, presence of an echogenic rim, tissue architecture, internal echo structure, absorption and elasticity. For statistical pattern recognition, the following parameters were used: form factor, mean grey level, signal-to-noise ratio, mean gradient and correlation from the co-occurrence matrix. At center 1, the most decisive parameter for differential diagnosis was distortion of tissue architecture (sensitivity, SN, 83%; specificity, SP, 92%) and, at center 2, relation to the adjacent tissue (SN 93%, SP 92%). Among texture parameters, best discrimination was achieved for correlation from the co-occurrence matrix at center 1 (SN 58%, SP 73%) and for form factor at center 2 (SN 93%, SP 77%). Among sonographic criteria, the highest contribution to the diagnosis was found for an unsharp border (odds ratio, OR, 12.2), architectural distortion (OR, 8.6), fixation to skin or chest wall (OR, 9.0) and fixation to adjacent breast parenchyma (OR, 8.8), according to texture analysis for parameters form factor (OR 4.0) and correlation from the co-occurrence matrix (OR 4.7). Ultrasonographic texture analysis can be helpful as an additional parameter in differential diagnosis of breast tumors, but did not reach differential diagnostic accuracy of sonomorphologic features.

Association between endometrial cancer and tamoxifen treatment of breast cancer

A retrospective cohort‐study in 4109 breast cancer patients was undertaken to determine how tamoxifen affected the risk of endometrial cancer. Data on 1701 tamoxifen‐treated women were analysed. Two thousand four hundred and eight non‐tamoxifen users served as control group. The occurrence of new primary uterine cancers was assessed by computerized linkage to the Austrian Cancer Registry. Twenty‐five women who subsequently developed endometrial cancer were identified. Eight uterine cancers occurred in the tamoxifen group, whereas 17 uterine cancers were found in the control group. The estimate of the relative risk (RR) showed an increased risk to develop endometrial cancer for the tamoxifen group RR 1.136 (95% CI 0.71; 1.80). Analysis of relevant confounding variables did not show any differences in the two groups.In conclusion, this retrospective study demonstrated a non‐significant increased risk of endometrial cancer in women receiving tamoxifen as treatment for breast cancer. However, the magnitude of RR and the absolute number of endometrial cancer cases in this long term observation demonstrate clearly that the clinical benefit of tamoxifen therapy greatly outweighs the risk.

CA 125 regression after two completed cycles of chemotherapy: lack of prediction for long-term survival in patients with advanced ovarian cancer.

The prognostic influence of CA 125 regression between the time point before surgery and after two completed courses of chemotherapy was studied in 210 patients with advanced ovarian cancer, and was compared to other well established prognostic factors. CA 125 blood samples were collected preoperatively (CA 125 pre) and 3 months after surgery (CA 125 3 mo) (at the beginning of the 3rd cycle of chemotherapy). The parameter CA 125 regression defined as log10 (CA 125 3 mo/CA 125 pre) was used for statistical analysis. In a survival analysis using a Cox proportional hazards model, CA 125 regression (P = 0.0001), residual tumour (P = 0.0001), age (P = 0.0095) and grading (P = 0.044) were independent variables, whereas stage of disease, histology, ascites and type of surgery failed to retain significance. Using log10 (CA 125 3 mo/CA 125 pre) as simple covariate in a Cox model showed a hazard ratio of 1.70 (95% confidence interval 1.32–2.19, P = 0.0001). However, a detailed analysis of the interaction of time with the prognostic factor CA 125 regression on survival revealed a strong time-dependent effect with a hazard ratio of more than 6 immediately after two courses of chemotherapy, whereas within approximately 1 year the hazard ratio for the surviving patients dropped quickly to the neutral level of 1. In summary, CA 125 regression is an independent prognostic factor for survival of women with advanced ovarian cancer and allows an identification of a high-risk population among patients with advanced ovarian cancer. However, the discriminating power of serial CA 125 for long-term survival seems to be temporary and prediction of individual patients outcome is far less precise.

Lunar phases and survival of breast cancer patients – a statistical analysis of 3,757 cases

The potential influence of lunar phases on human life has been widely discussed by the lay press. The purpose of this study was to find out whether the timing of surgery during particular lunar phases influences the survival of breast cancer patients. It has been postulated that breast cancer surgery performed during the waxing moon, or particularly at full moon, is associated with a poorer outcome. We tested this hypothesis by evaluating the overall survival for 3,757 consecutive patients with invasive breast cancer. All patients underwent either modified radical mastectomy or breast conserving surgery plus radiotherapy, followed by adjuvant cytotoxic or hormonal therapy. The date of definitive surgery was allocated to the lunar phases. 1,904 (50.7%) patients were operated on during the waxing moon and 1,853 (47.3%) during the waning moon. The median follow-up was 74 months (range 1–372 months). The mean age at primary surgery did not differ significantly in the two groups 58.39 (SD 13.14) versus 58.34 (12.75) (p > 0.05, t-test). Breast cancer stages at initial diagnosis were evenly distributed according to the lunar phases (p = 0.325; chi-square). Survival curves were plotted according to the method of Kaplan–Meier. No significant differences were observed when timing of surgery was allocated to the lunar phases (p = 0.4841, log-rank). Subgroup analysis of premenopausal patients revealed similar results (p = 0.2950, log-rank; n = 1072). Using multivariate Cox modelling, we found a significant association between the patients age, stage of disease and survival, whereas no association with survival was observed for the timing of surgery (RR = 1.062; 95% CI, 0.970–1.163; p = 0.1937). No significant differences in overall survival of breast cancer patients were observed when timing of breast cancer surgery during the lunar cycle was considered. Although this was not a prospective randomized trial, the statistical magnitude of the results do not support any recommendations for scheduling patients for surgery at any particular day of the lunar phase.

Tumor flow in malignant breast tumors measured by Doppler ultrasound: an independent predictor of survival

The purpose of this study was to investigate tumor blood flow in breast cancers with regard to its impact on the overall survival of patients. Tumor blood flow was assessed in seventy-four patients with primary breast cancer by the use of color-coded Doppler ultrasound techniques. Preoperatively obtained Doppler frequency spectra were analyzed for peak systolic flow velocity (Vmax). Color Doppler signals were detected in 71 (96%) of the breast tumors. Out of 74 patients, 17 experienced a relapse or distant metastasis, and 15 women had died due to breast cancer at the time of data analysis. The mean Vmax of the patients who had died was 0.27 m s−1, whereas survivors showed a mean Vmax of 0.16 m s−1(p=0.01.Vmax, nodal status, and progesterone receptor status remained the only significant factors of overall survival in the multivariate model, whereas tumor size, tumor grade, and estrogen receptor status failed to retain prognostic significance. Moreover, Vmax was identified as the most important prognostic marker for survival in our series. The five-year-survival was 82.3% in Vmax≤ 0.25 m s−1 patients versus 36.6% in women with tumor flow greater than 0.25 m s−1. Patients with Vmax > 0.25 m s−1 experienced a 4.33-fold increased risk of death secondary to the underlying disease.In summary, our data showed that tumor blood flow velocity measured by ultrasonography is an independent prognostic factor of survival in breast cancer patients. Furthermore, tumor flow velocity allows identification of patients at very high risk of death due to breast cancer. Large scale clinical trials should evaluate the clinical usefulness and future impact of this procedure for adjuvant treatment decisions.

TATI (tumour-associated trypsin inhibitor) as a marker of ovarian cancer.

In ovarian cancer patients a 6 kDa polypeptide, the tumour-associated trypsin inhibitor (TATI), can occur at elevated concentrations in both urine and serum. In this study pretreatment serum levels of TATI (cut-off point 21 ng ml-1) and CA 125 (cut-off points 35 U ml-1 and 65 U ml-1) were determined in 152 patients with epithelial ovarian cancer (115 primary and 37 recurrent) and in 267 women with benign pelvic diseases. The data obtained were correlated with the tumor stage, histological type and tumour grade. Overall, TATI showed a sensitivity of 64% and a specificity of 75%. The sensitivity and specificity of CA 125 > 35 U ml-1 were both 80%. Corresponding values for CA 125 > 65 U ml-1 were 70% and 87%. The combination of the two markers increased the sensitivity to 91% (CA 125 > 35 U ml-1) and 86% (CA 125 > 65 U ml-1), while the specificity dropped to 61% and 68% respectively. TATI was clearly superior in mucinous carcinomas of the ovary, the rate of true-positive findings in these neoplasms was 67% vs 42% for CA 125 > 35 U ml-1 and 33% for CA 125 > 65 U ml-1. Unlike CA 125, TATI correlated well with tumour grade. The combination of the two markers had a higher negative predictive value, i.e. 93% (CA 125 > 35 U ml-1) and 90% (CA 125 > 65 U ml-1) respectively. It is concluded that, while TATI cannot replace CA 125 in the diagnosis of malignant epithelial carcinomas of the ovaries, it is a valuable additional marker in cases of mucinous carcinomas and in combination with CA 125.