Effect of zoledronate on persisting isolated tumour cells in patients with early breast cancer.

BACKGROUND: There is strong evidence for the isolated tumour cells (ITCs) in the bone marrow of breast cancer patients having prognostic impact both at primary diagnosis and during recurrence-free follow-up. The goal of this study was to investigate the therapeutic efficacy of zoledronate on the persistence of ITC. PATIENTS AND METHODS: A total of 172 primary breast cancer patients without evidence of distant recurrence but detection of ITC in bone marrow were followed up. Zoledronate was administered every 4 weeks for 6 months to 31 patients who had completed surgery and adjuvant chemotherapy. In a matched-pair analysis, these patients were compared to 141 patients who did not receive additional zoledronate treatment. The bone marrow was re-examined after a median of 7.9 months (SD 0.89) and 11.5 months (SD 12.41; p=0.11), respectively. Patients were followed-up prospectively for a median of 39 months after the first aspiration. RESULTS: While ITCs were detected in all 172 patients at the time of first bone marrow aspiration, ITCs were detected in four patients (13%) following 6 months of zoledronate therapy in contrast to 38 patients (27%) of the control group (p=0.099). The reduction in cell numbers between the first and second aspiration reached statistical significance in the zoledronate group (p=0.02 vs. p=0.14). Persistent ITCs at the follow-up aspiration were associated with reduced recurrence-free survival (p=0.05). CONCLUSION: These results indicate a potential antineoplastic effect of the cell cycle-independent agent zoledronate on persisting ITCs in a dormant state.

Patients with recurrent breast cancer: does the primary axillary lymph node status predict more aggressive tumor progression?

BACKGROUND: The extent of axillary lymph node involvement represents the foremost important prognostic parameter in primary breast cancer, and, thus, is one of the main determinants for subsequent systemic treatment. Nevertheless, the relevance of the initial axillary lymph node status on survival after disease recurrence is discussed controversially. Persisting prognostic impact after relapse would identify lymph node status as a marker for tumor biology, in contrast to a simply time-dependent phenomenon. METHOD: Retrospective analysis of 813 patients with locoregional or distant recurrence of primary breast cancer, who were primarily diagnosed with their disease at the I. Frauenklinik, Ludwig-Maximilians-University, Munich, and the University Hospital in Berlin-Charlottenburg, Germany, between 1963 and 2000. To be eligible, patients were required to have been treated for resectable breast cancer free of distant disease at the time of primary diagnosis, and must have undergone systematic axillary lymph node dissection. Patients with unknown tumor size or nodal status were excluded from the study. All data were gathered contemporaneously and compared with original patients files, as well as the local cancer registry, ensuring high quality of data. The median observation time was 60 (standard deviation 44) months. RESULTS: At time of primary diagnosis, 273 patients (33.6%) were node-negative, while axillary lymph node metastases were detected in 540 patients (66.4%). In univariate analysis tumor size, axillary lymph node status, histopathological grading, hormone receptor status, as well as peritumoral lymphangiosis and haemangiosis carcinomatosa were significantly correlated with survival after relapse (all, P < 0.0001). Kaplan-Meier analysis estimated the median survival time after relapse in node-negative patients to be 42 months (31-52 months, 95% CI), and 20 months in patients with 1-3 axillary lymph node metastases (16-24 months, 95% CI), compared to 13 months in patients with at least 4 involved axillary nodes (12-15 months, 95% CI). Multivariate logistic regression analysis, allowing for tumor size, axillary lymph node status, histopathological grading, presence of lymphangiosis carcinomatosa, relapse site and disease-free interval confirmed all parameters, except of histopathological grading (P = 0.14), as significant, independent risk factors for cancer associated death. Subgroup analyses, accounting for site of relapse and duration of disease-free interval, confirmed primary lymph node status as independent predictor for cancer-associated death after relapse. CONCLUSION: Lymph node involvement at primary diagnosis of breast cancer patients predicts an unfavorable outcome after first recurrence, independently of the site of relapse and disease-free interval. These observations support the hypothesis that primary lymph node involvement is not a merely time-dependent indicator for tumor progression, but indicates tumors with aggressive biological behavior.

The prognostic impact of a prolonged second stage of labor on maternal and fetal outcome.

OBJECTIVE: While obstetrical management has changed significantly over years, the optimal duration of the second stage of labor still remains to be defined. The purpose of this study was to evaluate the effect of the duration of labor on fetal distress and maternal perinatal morbidity. METHODS: There were 1457 consecutive patients delivered of a singleton fetus in cephalic presentation beyond the 34th week of gestation at the I. Frauenklinik, Ludwig-Maximilians University, Munich between May 1999 and June 2000. The 257 patients (17.6%), who underwent cesarean section prior to or during labor, were excluded from the study. Of the 1200 vaginal deliveries, 1017 (84.8%) were normal spontaneous deliveries, while 183 (15.2%) were instrumentally assisted. Data were contemporaneously collected and analyzed for the presence of severe pelvic floor damage, maternal hemorrhage, maternal fever, delayed involution of the uterus, fetal acidosis and APGAR score, and the necessity for admitting the newborn to the intensive care unit (NICU). A second stage duration of > 2 hr was considered to be prolonged. RESULTS: The mean duration of the second stage of labor was 70 min (range 2-387, SD 73 min). For 952 patients (79.3%), the second stage was less than 2 h. For 47 patients (3.9%), it exceeded 4 h. A prolonged duration of the second stage was not associated with low Apgar scores 5 and 10 min postpartum (P = 0.76 and P = 0.38, respectively), a higher incidence of umbilical artery pH levels of < 7.20 (P = 0.60), nor with an increased rate of admission to the NICU (P = 0.24). A significant increase in the rate of maternal blood loss was noted after long second stages (1.84 g/dl median difference between the intrapartum and postpartum hemoglobin level) in comparison to patients with normal duration of second stage (0.79 g/dl), both by univariate (P < 0.0001) and multivariate (P < 0.001) analysis. The incidence of third degree anal sphincter tears was significantly correlated with a prolonged duration of second stage in univariate analysis (7.7%, P = 0.001), but not in multivariate analysis after allowing for duration of the second stage, maternal age, birth weight, episiotomy, and mode of delivery (P = 0.26). CONCLUSION: There is no evidence that prolonged second stage of labor is a serious disadvantage to the fetus, if adequate monitoring is provided. Because the increase of maternal morbidity in patients with prolonged labor may be partially attributed to a higher rate of operative procedures in these patients, interventions should not be solely based on the elapsed time after full cervical dilatation.