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Women undergoing treatment for breast cancer often experience a marked decrease in bone mineral density. This decrease is observed with chemotherapy as well as endocrine therapy and is more pronounced and rapid than normal postmenopausal bone loss. Pharmacologic intervention is, therefore, necessary in many cases to preserve bone health and prevent fractures. Many small studies have demonstrated that cancer therapy-induced bone loss (CTIBL) is effectively prevented by bone-targeted therapies, such as bisphosphonates and other inhibitors of bone resorption. Recently, several trials have confirmed the efficacy of bisphosphonates in the prevention of CTIBL in both premenopausal and postmenopausal women with early-stage breast cancer. In addition, concomitant treatment with zoledronic acid 4 mg every 6 months and standard adjuvant endocrine therapy has been reported to significantly improve disease-free survival and decrease disease recurrence in bone as well as other sites compared with standard therapy alone. Zoledronic acid treatment has also decreased residual tumor volume in the neoadjuvant setting. Furthermore, long-term follow-up of a single study in patients with bone marrow micrometastases from breast cancer revealed overall survival benefits for patients receiving clodronate 1600 mg/day compared with placebo; however, combined results from several trials of clodronate are inconclusive. Overall, a large body of evidence is accumulating to support the potential adjuvant benefits of bisphosphonates in the treatment of early-stage breast cancer. Results from ongoing studies are expected to further elucidate the benefits of bisphosphonates in maintaining bone health and improving clinical outcomes in patients with breast cancer.

Her-2/neu overexpression is an important prognostic parameter in breast cancer patients and has become a response predictor for trastuzumab treatment. Nevertheless, while trastuzumab is highly effective in many Her-2/neu overexpressing tumors, some do not respond. The reason for the differential effect is unknown, but it has been hypothesized that the complex interactions between Her-2/neu and other members of the EGFR family are involved in trastuzumab resistance. We have analyzed the protein expression of Her-2/neu, EGFR, and their activated forms, ptyr-1248 Her-2/neu, ptyr-845 EGFR and ptyr-1173 EGFR, in 57 Her-2/neu overexpressing breast tumors and investigated potential correlations between the receptors. By performing immunohistochemistry on paraffin-embedded tissue sections, we found that ptyr-845 EGFR was significantly co-expressed with Her-2/neu and ptyr-1248 Her-2/neu (p=0.043 and p=0.040, respectively), while ptyr-1173 EGFR was only correlated to Her-2/neu expression (p=0.042). Interestingly, EGFR and its activated forms were all significantly inversely correlated with PgR expression (p=0.011, p=0.033 and p=0.032, respectively), and ptyr-845 EGFR was also inversely correlated with ER expression (p=0.008). While we have previously shown that serum levels of the extracellular component of Her-2/neu are associated with tumoral ptyr-1248 Her-2/neu expression, we did not find a similar relationship between serum EGFR and intratumoral total/activated EGFR. We did, however, observe significantly higher levels of serum EGFR in women with 3+ overexpression of HER-2/neu (p=0.047). Taken together, we have demonstrated the activation pattern of EGFR and Her-2/neu in Her-2/neu overexpressing breast cancer. We suggest that EGFR inhibition might enhance the efficacy of trastuzumab by preventing cross-phosphorylation.

Objective: Anal sphincter injury and its sequelae are a recognized complication of vaginal childbirth. The aim of the present study was to identify risk factors for third- and fourth-degree perineal tears in patients undergoing either spontaneous or vaginal-assisted delivery by forceps routinely combined with mediolateral episiotomy., Study Design: We retrospectively reviewed 5377 vaginal deliveries based on the analysis of the obstetric database and patient records of our department during a 5-year period from 1999 to 2003. Cases and control subjects were chosen randomly and patients' records were reviewed for the following variables: maternal age, parity, gestational age, tobacco use, gestational diabetes or pregnancy-induced hypertension, use of peridural anesthesia, duration of first and second stages of labor, use of mediolateral episiotomy, forceps combined with mediolateral episiotomy, induction of labor, infant head diameter, shoulder circumference, and birth weight., Results: Of 5044 spontaneous vaginal deliveries 32 (0.6%) and of 333 assisted vaginal deliveries 14 (4.2%) patients sustained a perineal defect involving the external sphincter. An univariate analysis of these 46 cases and 155 randomly selected control subjects showed that low parity (P = .003; Mann-Whitney U test), prolonged first and second stages of labor (P = .001, P = .001), high birth weight (P = .031), episiotomy (P = .004; Fisher exact test), and forceps delivery (P = .002) increased the risk for sphincter damage. In multivariate regression models, only high birth weight (P = .004; odds ratio [OR] 1.68, 1.18-2.41, 95% confidence interval [CI]), and forceps delivery combined with mediolateral episiotomies (P < .001; OR 5.62, 2.16-14.62, 95% CI) proved to be independent risk factors. There was a statistical significant interaction of birth weight and head circumference (P = .012; OR 0.99, 0.98-0.99, 95% CI). Although the use of episiotomy conferred an increased risk toward a higher likelihood of severe perineal trauma, it did not reach statistical significance (P = .06; OR 2.15, 0.97-4.76, 95% CI)., Conclusions: In consistence with previous reports, women who are vaginally delivered of a large infant are at a high risk for sphincter damage. Although the rate of these complications was surprisingly low in vaginally assisted childbirth, the use of forceps, even if routinely combined with mediolateral episiotomy, should be minimized whenever possible.

Objective: To determine whether circulating levels of leptin differed between women with preeclampsia and women who had an uncomplicated pregnancy., Methods: Maternal and umbilical venous plasma leptin concentrations obtained at delivery were compared in 36 pairs of women with either preeclampsia or normal pregnancy, matched 1:1 for prepregnancy body mass index and fetal gestational age at delivery., Results: Prepregnancy body mass index was 21.1 +/- 2.1 kg/m2 in either study group (range 17.6-25.3 kg/m2 and 17.7-25.3 kg/m2 in the normal and preeclamptic group, respectively). Mean fetal gestational age at delivery was 40.1 +/- 1.3 weeks and 40.1 +/- 1.2 weeks in the normal and preeclamptic group, respectively. Median leptin concentrations were significantly lower (P <.0001) in women with preeclampsia (8.3 ng/mL, range 3.5-20.0 ng/mL) than in normal pregnant women (20.2 ng/mL, range 6.0-63.7 ng/mL). Median umbilical venous leptin was not significantly different between groups (preeclampsia 11.8 ng/mL, range 2.0-37.2 ng/mL; normal 7.6 ng/mL, range 1.6-24.3 ng/mL; P = .377). Umbilical venous leptin levels correlated positively with birth weight in both groups (preeclampsia rho = 0.501, P = .002; normal rho = 0.517, P = .001), whereas no correlations were found between maternal and fetal hormone concentrations. Maternal leptin concentrations did not correlate with birth weight., Conclusion: Our data suggest that the correlation between umbilical venous leptin concentration and birth weight is independent of the presence of preeclampsia. Given the inconsistency in literature concerning circulating leptin levels in preeclampsia, further studies should investigate the regulatory systems of leptin in preeclampsia.

Objective: To investigate the relationship between umbilical venous leptin concentration and gender in 20 pairs of newborns matched 1:1 for birth weight and gestational age at sampling., Materials: Blood samples were obtained from 40 women at delivery, identified as having an uncomplicated pregnancy. Umbilical venous blood samples were obtained from their newborns (20 males and 20 females) at birth. Specimens were analyzed using a human leptin 125-I radioimmunoassay., Results: Fetal leptin correlated positively with birth weight (rs = 0.541; P < .001). Umbilical venous leptin concentrations in female newborns (median: 10.7 ng/mL, range: 3.5-34.4 ng/mL) were significantly higher (P = .028) than in male newborns (median: 7.7 ng/mL, range: 2.0-19.3 ng/mL). There was no significant correlation between maternal and fetal leptin concentrations. Multiple logistic regression analysis revealed birth weight and gender to be independent factors influencing fetal cord leptin., Conclusion: Our results suggest that in the fetus, as in children and adults, gender and weight are the major determinants of circulating leptin levels.

Objective: To determine whether there is a difference in maternal leptin concentration and cord blood concentration, consistent with the hypothesis of a noncommunicating, two-compartement model of fetoplacental leptin regulation., Methods: Blood samples were collected from 139 women, identified as having an uncomplicated pregnancy, from an antecubital vein at delivery. Cord blood samples were taken from the umbilical vein. Leptin was measured by radioimmunoassay, and its relationship to fetal and maternal anthropometrics was assessed by Spearman correlation. Differences in maternal and cord blood leptin levels between male and female infants were tested with the Mann-Whitney Utest. Maternal and cord blood leptin were compared by the Wilcoxon signed rank test. The outcome measures were maternal and cord blood leptin at delivery, fetal birth weight, length, weight/length ratio, and ponderal index, maternal prepregnancy body mass index, pregnancy weight gain, relative weight gain, and body mass index at delivery., Results: No correlations were found between maternal and cord blood leptin concentrations. Fetal leptin level correlated with birth weight (rho = 0.665; P <.0001), length (rho = 0.490; P <.0001), ponderal index (rho = 0.260; P =.002), and weight/length ratio (rho = 0.625; P <.0001). Median leptin concentrations were higher in female (9.3 ng/mL, range 1.5-34.4 ng/mL) than in male (8.2 ng/mL, range 1.6-38.3 ng/mL) neonates, but this difference was statistically not significant. Logistic regression analysis showed a significant influence on umbilical venous leptin concentration for birth weight (P <.0001) but not for gender. Maternal leptin concentrations were significantly higher than cord leptin concentrations (P <.0005 for the male and female neonates and the entire group)., Conclusion: There was no correlation between maternal and cord leptin, which supports the hypothesis of a noncommunicating, two-compartment model of fetoplacental leptin regulation.