Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12.

BACKGROUND: Zoledronic acid (ZOL) plus adjuvant endocrine therapy significantly improved disease-free survival (DFS) at 48- and 62-month follow-up in the ABCSG-12 trial. We present efficacy results of a final additional analysis after 94.4 months. PATIENTS AND METHODS: Patients were premenopausal women who had undergone primary surgery for stage I/II estrogen-receptor-positive and/or progesterone-receptor-positive breast cancer with <10 positive lymph nodes, and were scheduled for standard goserelin therapy. All 1803 patients received goserelin (3.6 mg every 28 days) and were randomized to tamoxifen (20 mg/days) or anastrozole (1 mg/days), both with or without ZOL (4 mg every 6 months) for 3 years. The primary end point was DFS; recurrence-free survival and overall survival (OS) were secondary end points. RESULTS: After 94.4-month median follow-up (range, 0-114 months), relative risks of disease progression [hazard ratio (HR) = 0.77; 95% confidence interval (CI) 0.60-0.99; P = 0.042] and of death (HR = 0.66; 95% CI 0.43-1.02; P = 0.064) are still reduced by ZOL although no longer significant at the predefined significance level. Overall, 251 DFS events and 86 deaths were reported. Absolute risk reductions with ZOL were 3.4% for DFS and 2.2% for OS. There was no DFS difference between tamoxifen alone versus anastrozole alone, but there was a pronounced higher risk of death for anastrozole-treated patients (HR = 1.63; 95% CI 1.05-1.45; P = 0.030). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. CONCLUSION: These final results from ABCSG 12 suggest that twice-yearly ZOL enhances the efficacy of adjuvant endocrine treatment, and this benefit is maintained long-term. CLINICALTRIALSGOV: NCT00295646 (http://www.clinicaltrials.gov/ct2/results?term=00295646).

Does thyroid-stimulating hormone influence the prognosis of patients with endometrial cancer? A multicentre trial.

BACKGROUND: Thyroid function has been suggested to interfere with tumour biology and prognosis in different cancers. The present study was performed to investigate the impact of pre-therapeutic serum thyroid-stimulating hormone (TSH) levels on the prognosis of patients with endometrial cancer. METHODS: Pre-therapeutic serum TSH was investigated in 199 patients with endometrial cancer. After stratification in TSH risk groups, univariate and multivariable survival analyses were performed. RESULTS: Elevated TSH was independently associated with poor disease-specific survival in univariate/multivariable survival analyses (P=0.01 and P=0.03, respectively). CONCLUSION: Thyroid-stimulating hormone may serve as a novel and independent prognostic parameter for disease-specific survival in patients with endometrial cancer.

High nuclear grade and negative estrogen receptor are significant risk factors for recurrence in DCIS.

INTRODUCTION: Recommendations for adjuvant treatment of DCIS after breast conservation are controversial. We tried to identify further risk factors in a retrospective study of our own practice. PATIENTS AND METHODS: Three hundred and thirty-two patients treated by breast conservation between 1978 and 2001 at the Department of General Surgery, University of Vienna were analysed. Tumour size, nuclear grade, hormone receptors, p53, her-2/neu, multifocality, microinvasion and post-operative therapy (irradiation, tamoxifen or combination) were analysed for their influence on breast recurrence. RESULTS: Overall recurrence rate was 6.1% (8/132). For patients with DCIS showing high nuclear grade or negative estrogen receptor the risk for development of ipsilateral breast recurrence is significantly higher. Newer factors like p53 and her-2/neu do not have any prognostic significance. No recurrence was observed in patients treated by post-operative irradiation and tamoxifen. CONCLUSION: Nuclear grade remains the most significant factor for breast recurrence after DCIS. Hormone receptor status identifies a subset of patients with more favourable prognosis.

Sequential steroid hormone receptor measurements in primary breast cancer with and without intervening primary chemotherapy.

The objective of this analysis was to determine the accuracy of steroid receptor measurement in large core needle biopsies compared with surgically removed specimens and the influence of preoperative chemotherapy on hormone receptor status. We consecutively performed 722 large core needle biopsies in palpable lesions of the breast. The diagnosis of breast cancer was confirmed upon biopsy in 450 patients; 236 women underwent immediate surgery, and 214 patients received preoperative chemotherapy. We assessed estrogen (ER) and progesterone receptor (PR) in biopsy tissue and surgically removed specimens and calculated accuracy, sensitivity, specificity, the weighted kappa value and Spearman's rank correlation. The modulation of steroid receptor status in preoperatively treated patients was tested by Cochran-Mantel-Haenszel statistics. The accuracy of ER evaluation in the biopsy material of patients without intervening chemotherapy was 91%, sensitivity and specificity were 94% and 80% respectively. Accuracy, sensitivity and specificity were 86% in patients treated preoperatively. In terms of PR assessment, we obtained slightly inferior results: accuracy, sensitivity and specificity were 80%, 73% and 85% respectively in patients without preoperative treatment, and 79%, 48% and 92% respectively in patients undergoing preoperative therapy. Following preoperative chemotherapy, patients showed a significant increase in ER-negative (P=0.02) and PR-negative (P=0.0005) measurements. We have concluded from our results that ER and PR receptor measurement in core needle biopsy is a reliable basis in clinical practice for selecting patients for neoadjuvant endocrine treatment. Preoperative cytotoxic chemotherapy induced a significant extent of variation in the steroid receptor expression of breast cancer cells.

Contralateral breast cancer: molecular differentiation between metastasis and second primary cancer.

Previous cancer in one breast is a strong known risk factor for cancer in the contralateral breast. Differences in tumor histology and nuclear grading are applied to distinguish between a metastatic spread and a second primary cancer, although cancers of the breast often share the same histological features. Comparison of genetic alterations in paired tumors may provide the most reliable approach for discerning clonal relationships, hence uncovering the presence or absence of multiple primary cancers. We compared tumors from 33 patients with cancer in both breasts for mutations in the p53 gene. With this molecular approach, we were able to define the relationship within paired tumors in 13 patients. The paired tumors of two patients shared the same mutation, revealing the second lesion in one case as a contralateral metachronous lymph node metastasis appearing 29 months after first surgery, and in the other as a spread to the opposite breast. In 11 patients, mutations were either discordant or solely present in one of the lesions, confirming the diagnosis of bilateral breast cancer. Histopathological evaluation had failed to provide firm diagnosis in nine out of 11 instances on account of concordances in pathological parameters such as histological type and grading. In our study, we could show that bilateral breast malignancies most frequently represent two primary breast cancers. We could also demonstrate that contralateral breast cancer spread does occur. Standard pathological assessment allowed a firm diagnosis only in the presence of different histological types.

Diferenciales de mortalidad infantil por malformaciones congénitas con datos pareados: Chile 1993-1995 / Infant mortality differentials from congenital malformations with linked records: Chile 1993-1995

Background: The analysis of infant mortality from congenital malformations, which at present is the main group of causes of this mortality in Chile, suggests that it could be decreased with a good knowledge of its conditioning factors. Aim: To study infant mortality differentials from congenital malformations with linked records, in the 1993 to 1995 Chilean birth cohorts. Material and methods: Analysis of mortality differentials in 1993,1994 and 1995 birth cohorts. Multivariate logistic regression of mortality from congenital diseases. Results: Univariate analysis showed that mortality is highest in the Southern regions of the country (VII to XII) and in rural areas. It is also higher in children from older and from very young mothers, it increases along with the birth order of the child and decreases with increasing educational level of the mother. Multiple logistic regression analysis, confirmed the higher mortality in the Southern regions, aged mothers, high birth order of the child and low educational level of the mother. However no significant influence of rurality nor greater mortality in children of very young mothers was found. Conclusions: These results can be attributed to the fact that this type of analysis permits the control with other variables. Although the mortality data showed interesting relationships with the independent variables, a registry of all live births and stillbirths with congenital anomalies, that would provide greater numbers and data on non fatal anomalies, would be desirable to better study their causal factors

Locally advanced breast carcinoma: computer assisted semiquantitative analysis of color Doppler ultrasonography in the evaluation of tumor response to neoadjuvant chemotherapy (work in progress).

We aimed to evaluate objectively the value of color Doppler flow imaging in the assessment of response of locally advanced breast cancer to primary medical treatment by using a computer assisted semiquantitative method. Prior to and after neoadjuvant treatment, 17 patients with locally advanced breast carcinoma were prospectively evaluated by physical examination and computer assisted semiquantitative color Doppler ultrasonography. The results of clinical and color Doppler examination were finally correlated to the histopathologic evaluation of tumor response. The degree of concordance between posttherapeutic histopathologic results, clinical examination, and color Doppler assessment was evaluated by kappa statistics. Concordance was 0.474 (0.135-0.813) between histopathologic results and clinical posttherapeutic assessment and 0.870 (0.627-1.113) between histopathologic results and semiquantitative color Doppler examination. Objective semiquantitative assessment of tumor vascularity as displayed by color Doppler ultrasonography has potential as a functional tool for measuring tumor response to neoadjuvant chemotherapy.

Different transendothelial migration behaviour pattern of blood monocytes derived from patients with benign and malignant diseases of the breast.

BACKGROUND: In this study we compared the expression of selected monocyte surface antigens with the potential to transmigrate through an endothelial layer before and after surgery from breast cancer patients (CA) and patients with benign disease of the breast (BE). MATERIALS AND METHODS: Transmigration capacity of mononuclear cells was determined after isolation by Ficoll density gradient, layered over human umbilical vein endothelial cells and cultured in a two chamber plate added with fMLP as a chemotactic stimulus. We determined monocyte phenotye (HLA-DR, FcgRI/CD64, CR1/CD11b and LFA-1/CD11a) and the phagocytosis of E. coli by flow cytometry. RESULTS: Before surgery blood monocytes had an equal expression of the measured surface antigens, but were different in regard to their interaction with endothelial cells. Monocytes derived from CA had a higher transmigration potency than those of BE. Moreover, the migration through the endothelial cell layer created different populations of monocytes. Surgical stress modified transmigrated monocytes of BE into the direction of monocytes from CA. Phagocytic capacity of peripheral blood monocytes from CA was significantly diminished and was further reduced after surgery when measured in transmigrated cells. CONCLUSION: Our study shows that monocytes from CA and BE can be discriminated in regard to their interaction with endothelial cells.

[Clinical phase II-evaluation of neoadjuvant, cytostatic combination chemotherapy with docetaxel and epidoxorubicin in female breast cancer patients (T1-4, N0-2, M0)]. / Klinische Phase II-Evaluierung zur Kombinationstherapie mit Docetaxel und Epidoxorubicin in der neoadjuvanten, zytostatischen Chemotherapie bei Patientinnen mit Mammakarzinomen (T1-4, N0-2, M0).

BACKGROUND: Preoperative (neo-adjuvant) chemotherapy is very effective in downstaging primary tumors and moreover is able to prevent advancing metastatic growth early in the course of the disease. METHODS: We report on 38 patients with a median age of 54 years (range, 33-70 years) suffering from biopsy-proven breast cancer (T1-T4). Mastectomy had been considered the treatment of choice in all cases. The patients received 194 cycles of chemotherapy with docetaxel (75 mg/m2) and epidoxorubicin (75 mg/m2) on day 1, every 21 days, together with 30 million IU of G-CSF from days 3 to 10. Three to 8 cycles (median 5 cycles) of the treatment were administered until best response was achieved on mammography and clinical assessment. RESULTS: The neo-adjuvant chemotherapy was well tolerated and all patients completed the treatment regimen on an out-patient basis. During 194 cycles we observed leukopenia WHO grade IV only at one occasion (0.5%). WHO-grade III toxicity consisted of leukopenia (0.5%), diarrhoea (2%), and stomatitis (0.5%). Response to treatment was present in 85%, with 4 patients (11%) experiencing a pathological complete response (pCR) of the invasive tumor (T0: n = 2, DCIS: n = 2) and 28 patients (74%) showing a partial pathological response. In 21 patients (52%) a breast-conserving surgical procedure was possible. SUMMARY: We conclude that neo-adjuvant treatment of primary breast cancer with docetaxel and epidoxorubicin is safe and effective. By applying more chemotherapy cycles preoperatively it might even be possible to raise the rate of pCR and prolong survival.

[Indications and contraindications for breast preservation in patients with breast cancer]. / Indikationen und Kontraindikationen für die brusterhaltende chirurgische Therapie.

Roughly 70% of all patients with breast cancer can be treated by breast-preserving procedures under optimal circumstances. Risk factors for the development of local recurrences are age, angioinvasion, poor differentiation of the tumor, negative steroid hormone receptors, extensive intraductal component and positive margins. Contraindications for breast preservation are large tumors without remission after preoperative chemotherapy, multicentricity, extensive intraductal component, large ductal carcinoma in situ, inflammatory breast cancer after preoperative chemotherapy, Paget disease and local recurrence after breast-conserving surgery. Preoperative needle biopsy allows determination of nearly all of the risk factors. To further increase the rate of breast conservation, preoperative chemotherapy should be used more extensively.

A novel nonsense mutation of the PEX7 gene in a patient with rhizomelic chondrodysplasia punctata.

Mutations in the PEX7 gene encoding a peroxisome targeting signal 2 (PTS2) were identified in two patients with rhizomelic chondrodysplasia punctata (RCDP). A 7-year-old girl, the first Japanese individual to be diagnosed biochemically as a case of RCDP, had a novel nonsense mutation, R232ter, in the PEX7 gene, which had been inherited from her consanguineous parents. Another patient, a Chilean boy with RCDP, had compound heterozygous mutations of PEX7, L292ter and A218V, both of which have been documented. R232ter, which deletes all of the last two WP40 repeats in the PEX7 gene, is sufficient to inactivate functions of the PEX7 gene.

Randomized in vitro and in vivo evaluation of different biopsy needles and devices for breast biopsy.

In an experimental study (in vitro and in vivo) we evaluated the efficacy of various biopsy needles/devices for breast biopsy. In vitro, biopsies of five human cadaveric breast specimens were performed using 33 different needles/devices ranging from 14 to 20-gauge. Of these 33 needles/devices, 22 optimally performing needles were selected for the in vivo study. In the clinical part of the study, 44 breast lesions were randomly biopsied with each of the 22 needles/devices under stereotactic guidance. Tissue specimens were analysed quantitatively and qualitatively. Several automatic long-throw guns (Acecut, Asap, Biopty, Magnum) obtained greater tissue areas and had a better histopathologic score than the conventional type of a side-notch needle like Trucut, an aspiration needle like Surecut, or an end-cut needle like Autovac. The automatic long-throw guns performed better than the short-throw Monopty gun. Regardless of needle size (14-20-gauge), breast biopsies should be routinely performed with automated long-throw side-notch guns (Acecut, Asap, Biopty, Magnum).

Underlying disease as a predictor for rejection after liver transplantation.

BACKGROUND: As significantly more patients die of infection than of rejection after liver transplantation, we have to conclude that overimmunosuppression is common. Our analysis was performed to investigate underlying disease as an appropriate parameter for individually reduced immunosuppression. DESIGN: A consecutive series of patients receiving primary liver transplantation was analyzed with regard to acute rejection. SETTING: Department of transplantation surgery in a university hospital. PATIENTS AND METHODS: From 1988 to 1995, 252 patients received liver transplantation for posthepatitic cirrhosis, alcoholic cirrhosis, cholestatic disease, or hepatoma and were analyzed in a univariate and multivariate manner. MAIN OUTCOME MEASURE: The influence of various underlying diseases on the incidence of acute rejection. RESULTS: The estimated risk for freedom from acute rejection and analysis of cumulative rates of acute rejection stratified by group showed significant differences between the groups, except for alcoholic and posthepatitic cirrhosis. Severity of acute rejection episodes, as assessed by the need for rescue therapy, was similar in both univariate analysis and cumulative rates for alcoholic and posthepatitic cirrhosis. As expected, patients with cholestatic disease exhibited a significantly increased requirement for rescue therapy. For patients with hepatoma, a low incidence of initial and a high rate of repeated rescue therapy were observed. The varying immunological behavior within this group may have influenced both expansion of the tumor and severity of acute rejection. Multivariate analysis of potential risk factors identified underlying disease as a variable of independent prognostic significance for acute rejection and the need to receive rescue therapy. CONCLUSION: These results indicate the importance of taking the original disease into consideration where immunosuppressive therapy is concerned.

Haemophilus parainfluenzae liver abscess after successful liver transplantation.

Haemophilus parainfluenzae was isolated from a bile specimen and from an aspirate of a liver abscess in a 58-year-old liver-transplanted woman that was indicative of an invasion of the graft by an ascending route. Drug therapy, immunosuppression, rejection therapy, and Roux-en-Y choledochojejunostomy may have contributed to the septic course. Interdisciplinary cooperation was instrumental in diagnosis and successful management in this case.

[Neoadjuvant chemotherapy of patients with breast carcinoma]. / Neoadjuvante Chemotherapie bei Patientinnen mit Mammakarzinom.

Adjuvant therapy has shown to be of significant benefit in patients with breast cancer. Among the possibilities to further improve the results, preoperative chemotherapy is a promising tool. So far, we have treated 178 patients and found that downstaging permits breast conservation in 60% of patients who would otherwise undergo mastectomy. The significance of this method for further improvement of survival has to await results of ongoing trials.

Mortalidad infantil en Chile: el gran descenso / Infant mortality in Chile: the great descent

Infant mortality in Chile decreased from 120 to 12 per thousand between 1960 and 1994. Outstanding events of ths "great descent" are reviewed, based on past research and on updated information. Demographic and socioeconomic changes and improvements in health care that occured during this period of decline are shown. It is estimated that 30 percent of the reduction of infant mortality between 1972 and 1982 was due to the decreasing proportion of biths of high mortality risk, as a consequence of the fertility decline imitiated in the mid 60s. Possible explanations for the continuing decline of infant mortality during the economic crisis of 1975 and 1982 are discussed. Finally, neonatal and postneonatal mortality rates by causes are compared between 1994 and causes of death in extreme groups of infant mortality differentials by age of mother, bith order, gestational age, place of residence and educational level of the mother are shown

Coaxial technique: approach to breast core biopsies.

PURPOSE: To assess the feasibility of the coaxial core breast biopsy technique performed under stereotactic and ultrasound (US) guidance in vitro and in vivo. MATERIALS AND METHODS: Biopsies were performed in vitro and in vivo with a coaxial technique. In vitro, the true needle-tip deviation was measured with a breast phantom on a stereotactic device with alteration of x and y axes. In vitro US studies were performed to evaluate the optimal technique for harvesting sufficient material for histologic work-up. In 205 patients, coaxial biopsy was performed in 210 suspicious lesions under US (61 lesions) or stereotactic (patient in the sitting position, n = 67; patient in the prone position, n = 82) guidance. In addition, the coaxial system was used for preoperative localization. Surgery and histologic work-up were performed in all cases. RESULTS: In vitro, the true needle-tip deviation was found to be less than indicated on the stereotactic device. A factor was introduced to correct this error. For US guidance, angulation or rotation of the coaxial needle within the lesion proved to be the best technique to increase the size of histologic specimen. Of the 210 lesions, 112 were benign and 98 were malignant. Agreement between biopsy results and final postsurgical histologic analysis was found in 205 cases (98%). CONCLUSION: The coaxial breast biopsy technique is an accurate, simple, and time-saving method performed under stereotactic or US guidance.