Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients.

PURPOSE: Activation or overexpression of HER-2/neu is associated with up-regulation of vascular endothelial growth factor (VEGF) in human breast cancer cells in vitro. Preclinical experiments indicate that increased expression of VEGF may in part mediate the biologically aggressive phenotype of HER-2/neu-overexpressing human breast cancer. It was the purpose of this study to: (a). evaluate the association between HER-2/neu and VEGF expression in a large clinical cohort of primary breast cancer patients; (b). compare the prognostic significance of VEGF isoforms; and (c). analyze the combined effects of HER-2/neu and VEGF on clinical outcome. EXPERIMENTAL DESIGN: HER-2/neu and VEGF were measured by ELISA in primary breast tumor tissue lysates from 611 unselected patients with a median clinical follow-up of 50 months. At least six VEGF isoforms consisting of 121, 145, 165, 183, 189, or 206 amino acids are generated as a result of alternative splicing. The VEGF(121-206) ELISA uses antibodies that bind to VEGF(121) and, therefore, detects all of the VEGF isoforms with 121 and more amino acids. The VEGF(165-206) ELISA uses antibodies that bind to VEGF(165) and, therefore, detects all of the VEGF isoforms with 165 and more amino acids. VEGF(121-206) and VEGF(165-206) were analyzed both as continuous and categorical variables, using detectable expression as a cutoff for positivity. Cell lines with defined HER-2/neu expression levels were used to establish a cutoff point for HER-2/neu overexpression in breast tumor samples. RESULTS: Our findings indicate a significant positive association between HER-2/neu and VEGF expression. VEGF(121-206) and VEGF(165-206) expression was detectable in 88 (77.2%) and 100 (87.7%), respectively, of the 114 patients with HER-2/neu-overexpressing tumors, in contrast to 271 (54.5%) and 353 (71.0%), respectively, of the 497 patients with nonoverexpressing tumors (chi(2) test: P < 0.001 for both VEGF(121-206) and VEGF(165-206)). VEGF(121-206) and VEGF(165-206) demonstrate a comparable prognostic significance for survival in unselected primary breast cancer patients (univariate analysis: VEGF(121-206), P = 0.0068; VEGF(165-206), P = 0.0046; multivariate analysis: VEGF(121-206), P = 0.1475; VEGF(165-206), P = 0.1483). When the analyses were performed separately for node-negative and node-positive patients, VEGF(121-206) and VEGF(165-206) were of prognostic significance for survival only in node-positive patients (univariate analysis: VEGF(121-206), P = 0.0003; VEGF(165-206), P = 0.0038; multivariate analysis: VEGF(121-206), P = 0.0103; VEGF(165-206), P = 0.0150). A biological concentration-effect relationship between VEGF expression and survival (VEGF(121-206), P = 0.0280; VEGF(165-206,) P = 0.0097) suggests that VEGF levels, as determined by ELISA, could be of importance as a predictive marker for therapeutic strategies that target VEGF. Combining HER-2/neu and VEGF(121-206)/VEGF(165-206) results in additional prognostic information for survival (VEGF(121-206), P = 0.0133; VEGF(165-206), P = 0.0092). CONCLUSION: The positive association between HER-2/neu and VEGF expression implicates VEGF in the aggressive phenotype exhibited by HER-2/neu overexpression, and supports the use of combination therapies directed against both HER-2/neu and VEGF for treatment of breast cancers that overexpress HER-2/neu.

[Right and ethics in reproductive medicine--medical and ethical aspects]. / Recht und Ethik in der Reproduktionsmedizin--Arztliche und ethische Aspekte.

Legality and ethics in reproductive medicine are interdependent. Whether ethics degenerates into an ethics of convenience and adaptation, or into an ethics that always comes too late, depends on each doctor and researcher. Our medical care requires legal guidelines. There is not only a responsibility for research, but also one for engaging in research. This position is presented in four sections: on reproductive medicine, the moral status of the embryo, the research on spare embryos and in a section on reproductive medicine in Europe.

[Sentinel lymph node biopsy in breast cancer: state of the art]. / Die Sentinellymphknoten-Entfernung beim Mammakarzinom: Derzeitiger Stand.

Axillary lymph node excision of level I and II with at least 10 lymph nodes is the operative gold standard for invasive breast cancer. Axillary lymph node excision is a diagnostic procedure for histopathologic tumor classification, for assessment of prognosis, local tumor control and adjuvant therapy decision. The sentinel node biopsy is a minimal-invasive procedure to determine the axillary lymph node status by excision of one or more sentinel nodes. This procedure is being increasingly implemented in breast cancer surgery. The classical axillary lymph node excision can be replaced by sentinel node biopsy if sentinel nodes are free of invasion in the intraoperative as well as in the final histopathological report. Sentinel node biopsy can become an operative routine procedure only in a quality-controlled environment.

[Cervical incompetence in multifetal gestation: diagnosis and prophylaxis]. / Diagnostik und Prophylaxe der Cervixinsuffizienz in der Mehrlingsschwangerschaft.

OBJECTIVE: Preterm birth following cervical incompetence threatens infants of multiple gestation. The questions at hand are whether we can validate a sonographic early detection system and if prophylactically intended strategies, such as cervical cerclage, potentially influence pregnancy management and/or perinatal outcome. METHODS: Multifetal pregnancies surveyed with three-dimensional ultrasound and pregnancies treated with cervical cerclage were compared to controls. RESULTS: Volumetry of the cervix was possible in all 34 examinations performed. In contrast, two-dimensional cervical length assessment could not be obtained in 6% because the presenting fetal part obstructed the sonographic plane. Mean cervical length was 28.7 mm (SD 7.7). Mean cervical volume was 30.0 cm3 (SD 16.0). A significant correlation was found between mean two-dimensional cervical length and mean cervical volume as both parameters decreased with gestational age (p = 0.01). Prophylactic cervical cerclage was used in 17% of triplet pregnancies studied at a mean gestational age of 16 + 2 weeks (98-138 days). In 50% of the quadruplet/quintuplet pregnancies studied, the cerclage was performed at a mean gestational age of 15 + 2 weeks of gestation (78-152 days). The time interval from operation to delivery was 106 days (62-119) for triplets and 96 days (57-142) for quadruplets/quintuplets. Prophylactic cervical cerclage did not prolong pregnancies compared to controls. With respect to the need for hospitalization or intravenous tocolysis or perinatal outcome parameters, no benefit was achieved. CONCLUSIONS: The results disclaim a positive impact of prophylactic cervical cerclage on the course of a multifetal pregnancy and/or perinatal outcome. On the other hand, early non-invasive diagnosis of cervical incompetence enables a risk-adapted conservative pregnancy management.

[Asymptomatic uterine rupture after two spontaneous vaginal deliveries following prior cesarean section]. / Gedeckte Uterusruptur nach zweimaligem Spontanpartus im Status nach Sectio caesarea bei der ersten Entbindung.

We present the case of an almost asymptomatic uterine rupture after two consecutive vaginal deliveries after a prior cesarean delivery (first child). Uterine rupture is rare even after a prior cesarean delivery, permitting a trial of labor after a cesarean delivery in spite of the increased risk of uterine rupture. Vaginal birth after previous cesarean delivery, however, demands a cautious approach. Appropriate recommendations have been published by the ACOG and the 'AG fOr fetomaternale Medizin' (a branch of the German Society of Obstetrics and Gynaecology). In our case diagnosis was made by an vaginal ultrasound examination 7.5 weeks after an uncomplicated vaginal delivery. An additional MRI examination did not result in substantial extra information. For that reason it will be indicated only in exceptional cases. To answer the question whether a vaginal ultrasound examination should routinely be offered after an uncomplicated vaginal delivery with a prior cesarean delivery in the history to preclude uterine rupture further studies are necessary.

EMG-biofeedback assisted pelvic floor muscle training is an effective therapy of stress urinary or mixed incontinence: a 7-year experience with 390 patients.

PURPOSE: The aim of the study was to determine the short- and long-term efficacy of an intensive and EMG-biofeedback-assisted pelvic floor muscle training (PFMT) program as a therapy of female stress or mixed urinary incontinence. MATERIALS AND METHODS: All women with stress or mixed urinary incontinence treated in the pelvic floor reeducation program at our clinic between September 1996 and March 2003 were included. EMG-biofeedback assisted PFMT was performed by specially trained therapists (one registered nurse and one midwife). Electric stimulation preceded PFMT if the pelvic floor muscle contractions were considered too weak for active training (Oxford < 2). Examinations included among others: conventional urodynamic studies prior to therapy, a stress provocation test (cough test), and determination of maximal pelvic floor muscle strength (Oxford-grading and electric EMG-potential). A retrospective chart review was performed. A questionnaire was administered for long-term follow-up. RESULTS: Four hundred and thirty four women attended our PFR-program in this 7-year period. All 390 women with stress (80%) or mixed (20%) urinary incontinence were evaluated. Mean age: 52 years. Mean duration of incontinence: 6.7 years. Two hundred and sixty three women completed the training (group 1, average number of training sessions: 8.7), 127 patients ended therapy prematurely (group 2, average number of training sessions: 4.1). Short-term results at the end of the PFR-program are available for group 1. There was a statistically significant improvement of the stress provocation test (cough test). The data before the therapy was 141x SUI degrees III (60%); 50x SUI degrees II (21%), 24x SUI degrees I (10%), 20x SUI degrees 0 (9%) as opposed to after the therapy 9x SUI degrees III (5%), 34x SUI degrees II (19%), 48x SUI degrees I (26%), 91x SUI degrees 0 (50%). There was a significant increase in the Oxford-score by 1.2 points (2.9-4.1; P<0.001). Self-reported improvement of incontinence symptoms was 95%. The electric EMG-potentials almost doubled (11.3-20.5 muV; P<0.001). Long-term results (questionnaire) for all patients: the average follow-up time was 2.8 years (range: 3 months to 7 years). Three hundred and twelve (80%) of the questionnaires returned. Seventy-one percent of them self-reported a persisting improvement of their incontinence symptoms. Thirteen percent of all women underwent incontinence surgery following the completion of conservative therapy (9.2% group 1, 25% group 1; P<0.001). CONCLUSIONS: An intensive and EMG-biofeedback assisted PFMT is very effective. Often, avoidance of surgery is possible.

Episiotomy and perineal tears presumed to be imminent: the influence on the urethral pressure profile, analmanometric and other pelvic floor findings--follow-up study of a randomized controlled trial.

BACKGROUND: The influence of the restrictive use of episiotomy at perineal tears judged to be imminent on the urethral pressure profile, analmanometric, and other pelvic floor findings is unknown. METHODS: Follow-up study of a randomized controlled trial with two perineal management policies includes the use of episiotomy: (a) only for fetal indications and (b) in addition at a tear presumed to be imminent. Participants were 146 primiparous women with an uncomplicated singleton pregnancy >34 weeks of gestation. For the intention-to-treat analysis, 68 women after vaginal delivery were included who delivered a live full-term baby between January 1999 and September 2000. OUTCOME MEASURES: Maximum urethral closure pressure (MUCP, cmH2O), functional urethral length (mm), maximum anal pressure (MAP, mmHg), functional anal sphincter length (ASL, mmHg) at rest and during contraction, and pelvic floor muscle strength (5-grade Oxford score) are the outcome measures. The rate of dyspareunia, urinary incontinence, and anorectal incontinence was documented. RESULTS: At a mean follow up of 7.3 months, there were no statistically significant differences between the two groups (a versus b): mean MUCP at rest (98 versus 101 cmH2O), during contraction (95 versus 103 cmH2O), mean MAP at rest (113 versus 121 mmHg), during contraction (143 versus 166 mmHg), mean ASL at rest (50 versus 50 mmHg), during contraction (42 versus 45 mmHg), mean pelvic floor muscle strength (2.2 versus 2.6), no pain during sexual intercourse (79 versus 67%), prevalence of urinary incontinence (48 versus 27%), and anorectal incontinence (19 versus 24%). CONCLUSIONS: Episiotomy at a perineal tear presumed to be imminent does not have any advantage with regard to pelvic floor function and should be avoided.

Evaluation of prognostic factors following flow-cytometric DNA analysis after cytokeratin labelling: I. Breast cancer.

In gynecologic oncology valid prognostic factors are necessary to estimate the course of disease and to define biologically similar subgroups for analysis of therapeutic efficacy. The presented study is a prospective study concerning prognostic significance of DNA ploidy and S-phase fraction in breast cancer following enrichment of tumor cells by cytokeratin labelling. Epithelial cells were labeled by FITC-conjugated cytokeratin antibody (CK 5, 6, 8, and CK 17) prior to flow cytometric cell cycle analysis in 327 fresh specimens of primary breast cancer. Univariate analysis in breast cancer detected the prognostic significance of DNA-ploidy, S-phase fraction and CV (coefficient of variation) of G(0)G(1)-peak of tumor cells for clinical outcome, especially for nodal-negative patients. Multivariate analysis could not confirm prognostic evidence of DNA-ploidy and S-phase fraction. In conclusion, in breast cancer no clinical significance for determination of DNA-parameters was found.

Evaluation of prognostic factors following flow-cytometric DNA analysis after cytokeratin labelling: II. Cervical and endometrial cancer.

In gynecologic oncology valid prognostic factors are necessary to define biologically similar subgroups for analysis of therapeutic efficacy. This study is the first published prospective study concerning prognostic significance of DNA ploidy and S-phase fraction in cervical and endometrial cancer following enrichment of tumor cells by cytokeratin labelling. Epithelial cells were labeled by FITC-conjugated cytokeratin antibody (CK 5, 6, 8, and CK 17) prior to flow cytometric cell cycle analysis in 91 specimens of cervical cancer and 73 samples of endometrial cancer. In cervical cancer neither DNA-ploidy nor S-phase fraction were relevant prognostic parameters. But CV of the G(0)G(1)-peak showed prognostic relevance in cervical cancer cells, even in multivariate analysis. This interesting observation, however, seems to have no therapeutic consequence due to the small discrimination capacity of CV. In endometrial carcinoma, gross DNA-aneuploidy (DNA-index > 1.3) and a high percentage of proliferating cells (>75th percentile) were univariate and multivariate highly significant prognostic factors for recurrence-free survival. Especially DNA-aneuploidy (DI>1.3) is one of the most important independent molecular biological prognostic factors. While diagnostic curettage we could identify risk patients even preoperatively by determination of the prognostic factors like histologic tumor type, grading, cervical involvement and DNA-ploidy. Thereby these patients could be treated primarily in an oncologic center. In conclusion, our investigations showed that the determination of DNA-ploidy should be done in endometrial carcinoma. In cervical cancer no clinical significance for determination of DNA-parameters was found.

Episiotomy and perineal tears presumed to be imminent: randomized controlled trial.

BACKGROUND: The indication of the restricted use of episiotomy at tears presumed to be imminent is not clear. METHODS: Randomized controlled trial with two perineal management policies. Use of episiotomy: (a). only for fetal indications and (b). in addition at a tear presumed to be imminent. PARTICIPANTS: 146 primiparous women with an uncomplicated singleton pregnancy at >34 weeks of gestation. For the intention-to-treat analysis those 109 women were included who vaginally delivered a live full-term baby between January 1999 and September 2000: 49 women in group a, 60 in group b. OUTCOME MEASURES: Reduction of episiotomies, increase of intact perinea or only minor perineal trauma (intact perineum and first-degree tears), third-degree tears, anterior perineal trauma, perineal pain in the postpartum period, pH of the umbilical artery, Apgar scores, maternal blood loss. RESULTS: Episiotomy rates were 41% in group a and 77% in group b (p < 0.001). Women in the restrictive policy group had a greater chance of an intact perineum (29% vs. 10%; p = 0.023) or only minor perineal trauma (39% vs. 13%; p = 0.003) and had significant lower pain scores postpartum at different activities. There were no statistically significant differences with regard to third-degree tears, anterior trauma, pre- and postpartum hemoglobin concentrations, Apgar scores and pH of the umbilical artery. CONCLUSIONS: Avoiding episiotomy at tears presumed to be imminent increases the rate of intact perinea and the rate of only minor perineal trauma, reduces postpartum perineal pain and does not have any adverse effects on maternal or fetal morbidity.

Maternal and neonatal morbidity of emergency caesarean sections with a decision-to-delivery interval under 30 minutes: evidence from 10 years.

PURPOSE: The purpose was to investigate the decision-to-delivery interval for emergency caesarean section and to compare the perioperative maternal and neonatal morbidity to that of intrapartum non-emergent caesarean section. MATERIALS AND METHODS: A cohort study was designed evaluating 109 women undergoing 'crash' emergency caesarean section and 109 controls from 1988 to 1997 in a University hospital. All emergency caesarean sections were performed in the delivery room. Controls were matched by gestational age. Retrospective collection of data relating to indication, maternal and neonatal outcome of both groups was conducted. Time intervals between decision to deliver and actual delivery were collected for all emergency deliveries. RESULTS: The emergency caesarean section cohort represented a high risk group with a mean gestational age of 34.8 weeks and a high number of patients with preterm labour (29.3%). All 109 emergency caesarean sections were achieved within a decision-to-delivery time of 30 min. Severe maternal haemorrhage was significantly higher mainly because of underlying obstetrical complications such as placenta praevia, placental abruption, and others resulting in a blood transfusion rate of 10.1%. Procedure related and infectious maternal morbidity, however, was not significantly increased. All women undergoing the emergency procedure received perioperative antibioprophylaxis. Mean umbilical arterial blood pH and Apgar scores were significantly lower in infants delivered by emergency caesarean section but there was no difference in the admission to the NICU. CONCLUSIONS: Emergency caesarean section performed in the delivery room may result in a decision-to-delivery time of less than 30 min without detrimental perioperative effects on mother or infant.

Pregnancy complications, obstetric risks, and neonatal outcome in singleton and twin pregnancies after GIFT and IVF.

PURPOSE: In vitro fertilization (IVF) and to a lower extent gamete intra-fallopian transfer (GIFT) have become routine infertility treatments in industrialized countries. Our purpose is to compare the obstetric and neonatal characteristics of singleton and twin pregnancies after GIFT and IVF with those conceived spontaneously. METHODS: This case-control study was conducted in a tertiary care medical center. The 322 singleton and 78 twin pregnancies after GIFT or IVF from 1991 through 1996 were evaluated and compared with each other, and with a control group that conceived spontaneously and matched for parity, maternal and gestational age. Statistical significance of differences was assessed by chi(2) test or two-tailed Fisher exact test. Continuous variables were compared by the paired t-test. RESULTS: Pregnancy-induced hypertension (PIH) and vaginal bleeding were significantly more frequent maternal complications in the GIFT/IVF singleton groups compared to controls. In twin pregnancies the rate of cesarean sections, vaginal bleeding and preterm labor were more common after GIFT/IVF but did not reach statistical significance. Assisted reproduction was associated with low birth weight only in twin pregnancies when controlled for confounding variables, however perinatal outcome was comparable. There was no significant difference in the outcome measures between GIFT and IVF pregnancies. CONCLUSION: After controlling for parity, maternal and gestational age, singleton pregnancies conceived by GIFT/IVF are at increased obstetrical risk, however the perinatal outcome is comparable despite a lower average birth weight.

Uterine dehiscence in a nullipara, diagnosed by MRI, following use of unipolar electrocautery during laparoscopic myomectomy: Case report.

Uterine scar dehiscence following laparoscopic myomectomy (LM) is a rare event. We present a case of an magnetic resonance imaging-diagnosed uterine dehiscence in a primigravid patient at 29 weeks gestation, following a laparoscopic subserosal myomectomy, performed using unipolar electrocoagulation. Pregnant patients with a history of prior surgery where unipolar electrocoagulation is used on the uterus should be closely followed throughout pregnancy and uterine dehiscence or rupture should be part of the differential diagnosis when they present with abdominal pain.

Multifetal gestation--maternal and perinatal outcome of 112 pregnancies.

PURPOSE: Multifetal pregnancy reduction is a widespread "therapy" to diminish the risk of prematurity and adverse outcome for the survivors in higher order multiple gestation. The aim of our study was to determine the maternal and neonatal outcome of multifetal pregnancies under a conservative pregnancy management. STUDY DESIGN: A retrospective review of 112 multifetal pregnancies is presented. All higher order multiple pregnancies delivered after 25 weeks of gestation and managed at a single institution between 1982 and 1999 are included. RESULTS: Triplets, quadruplets and quintuplets were delivered at a mean gestational age of 31 + 5, 29 + 5 and 28 + 4 weeks, respectively. The perinatal mortality was 14 for triplets and 36 for quadruplets. No quintuplet died in the perinatal period. Respiratory distress syndrome occurred in 23% of triplets, 65% of quadruplets and 75% of quintuplets, intracranial hemorrhage was diagnosed in 14% of triplets, 15% of quadruplets and 10% of quintuplets and retinopathy of prematurity was found in 10% of triplets, 9% of quadruplets and 25% of quintuplets. DISCUSSION: Despite a low neonatal mortality, morbidity of higher order multiple gestations remains significant. Mortality and morbidity are related to preterm delivery but do not exceed the rates of singletons or twins of an identical gestational age. Favorable prognostic landmarks are a gestational age >30 weeks and a number of fetuses per pregnancy < or =4. CONCLUSION: The risks of multifetal pregnancies are significant. Therefore, evidence-based counseling of couples seeking treatment for infertility and prevention of higher order multiple pregnancies through the prudent use of reproductive techniques attains paramount importance.

Multivariate analysis of the prognostic significance of DNA-ploidy and S-phase fraction in ovarian cancer determined by flow cytometry following detection of cytokeratin-labeled tumor cells.

OBJECTIVE: The outcome of patients with advanced ovarian cancer is poor despite aggressive therapy including surgery and multiagent chemotherapy. Valid prognostic factors are necessary to estimate the course of the disease and to define biologically similar subgroups for analysis of therapeutic efficacy. METHODS: This study is the first published prospective study concerning the prognostic significance of DNA-ploidy and S-phase fraction in ovarian cancer following enrichment of tumor cells by cytokeratin labeling. Epithelial cells were labeled by FITC-conjugated cytokeratin antibody (CK 5, 6, 8, and 17) prior to flow cytometric cell cycle analysis in 129 fresh specimens of primary ovarian cancer. RESULTS: Recurrence-free survival of patients with DNA-diploid primary ovarian cancer was significantly better compared to that of patients with DNA-aneuploid tumors in univariate analysis (47% vs 18%, P = 0.01). The tumor-dependent overall survival of patients with DNA-diploid tumors was 57% compared to 30% with DNA-aneuploid tumors (P = 0.04). In FIGO stage III ovarian cancer DNA-ploidy, optimized by cytokeratin gating for tumor cells, achieved independent prognostic significance. No significance was found for S-phase fraction. However, despite convincing methodological advantages in the detection of DNA-aneuploid subpopulations the clinical significance of cytokeratin gating of epithelial cells was only marginal. CONCLUSION: DNA-ploidy has been shown to be as powerful or even more so in comparison to postoperative residual tumor in multivariate analysis for predicting clinical outcome in advanced ovarian cancer. Thus, determination of DNA-ploidy should be introduced to currently recruiting phase III studies for therapy of ovarian cancer for better definition of prognostic subgroups.