Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates.

STUDY QUESTION: What is the success rate in terms of ovarian activity (menstrual cycles) as well as pregnancy and delivery rates 1 year after orthotopic ovarian transplantations conducted in a three-country network? SUMMARY ANSWER: In 49 women with a follow-up >1 year after transplantation, the ovaries were active in 67% of cases and the pregnancy and delivery rates were 33 and 25%, respectively. WHAT IS KNOWN ALREADY: Cryopreservation of ovarian tissue in advance of cytotoxic therapies and later transplantation of the tissue is being performed increasingly often, and the total success rates in terms of pregnancy and delivery have been described in case series. However, published case series have not allowed either a more detailed analysis of patients with premature ovarian insufficiency (POI) or calculation of success rates based on the parameter 'tissue activity'. STUDY DESIGN, SIZE, DURATION: Retrospective analysis of 95 orthotopic transplantations in 74 patients who had been treated for cancer, performed in the FertiPROTEKT network from 2008 to June 2015. Of those 95 transplantations, a first subgroup (Subgroup 1) was defined for further analysis, including 49 women with a follow-up period >1 year after transplantation. Of those 49 women, a second subgroup (Subgroup 5) was further analysed, including 40 women who were transplanted for the first time and who were diagnosed with POI before transplantation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Transplantation was performed in 16 centres and data were transferred to the FertiPROTEKT registry. The transplantations were carried out after oncological treatment had been completed and after a remission period of at least 2 years. Tissue was transplanted orthotopically, either into or onto the residual ovaries or into a pelvic peritoneal pocket. The success rates were defined as tissue activity (menstrual cycles) after 1 year (primary outcome) and as pregnancies and deliveries achieved. MAIN RESULTS AND THE ROLE OF CHANCE: The average age of all transplanted 74 women was 31 ± 5.9 years at the time of cryopreservation and 35 ± 5.2 at the time of transplantation. Twenty-one pregnancies and 17 deliveries were recorded. In Subgroup 1, tissue was cryopreserved at the age of 30 ± 5.6 and transplanted at 34 ± 4.9 years. Ovaries remained active 1 year after transplantation in 67% of cases (n = 33/49), the pregnancy rate was 33% (n = 16/49) and the delivery rate was 25% (n = 12/49). In Subgroup 5, tissue was cryopreserved at the age 30 ± 5.9 years and transplanted at 34 ± 5.2 years. Ovaries remained active 1 year after transplantation in 63% of cases (n = 25/40), the pregnancy rate was 28% (n = 11/40) and the delivery rate was 23% (n = 9/40). The success rates were age dependant with higher success in women who cryopreserved at a younger age. In Subgroup 5, tissue was exclusively transplanted into the ovary in 10% (n = 4/40) of women and into a peritoneal pocket in 75% (n = 30/40), resulting in spontaneous conceptions in 91% of patients (n = 10/11). LIMITATIONS, REASONS FOR CAUTION: The data were drawn from a retrospective analysis. The cryopreservation and transplantation techniques used have changed during the study period. The tissue was stored in many tissue banks and many surgeons were involved, leading to heterogeneity of the procedures. However, this does reflect the realistic situation in many countries. Although patients with POI were evaluated before transplantation to allow specific analysis of the transplanted tissue itself, the possibility cannot be excluded that residual ovarian tissue was also reactivated. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest case series worldwide to date and it confirms that cryopreservation and transplantation of ovarian tissue can be a successful option for preserving fertility. Persistent tissue activity 12 months after transplantation suggests that the pregnancy and delivery rates may increase further in the future. As transplantation into the peritoneum results in a high success rate, this approach may be an alternative to transplantation into the ovary. However, in order to establish the best transplantation site, a randomized study is required. STUDY FUNDING/COMPETING INTEREST: This study was in part funded from the Deutsche Forschungsgemeinschaft (# DI 1525) and the Wilhelm Sander Foundation (2012.127.1) and did not receive any funding from a commercial company. No competing interests. TRIAL REGISTRATION NUMBER: None.

Single deepest vertical pocket or amniotic fluid index as evaluation test for predicting adverse pregnancy outcome (SAFE trial): a multicenter, open-label, randomized controlled trial.

OBJECTIVE: To determine whether the amniotic fluid index (AFI) or the single deepest vertical pocket (SDP) technique for estimating amniotic fluid volume is superior for predicting adverse pregnancy outcome. METHODS: This was a multicenter randomized controlled trial including 1052 pregnant women with a term singleton pregnancy across four hospitals in Germany. Women were assigned randomly, according to a computer-generated allocation sequence, to AFI or SDP measurement for estimation of amniotic fluid volume. Oligohydramnios was defined as AFI ≤ 5 cm or the absence of a pocket measuring at least 2 × 1 cm. The diagnosis of oligohydramnios was followed by labor induction. The primary outcome measure was postpartum admission to a neonatal intensive care unit. Further outcome parameters were the rates of diagnosis of oligohydramnios and induction of labor (for oligohydramnios or without specific indication), and mode of delivery. RESULTS: Postpartum admission to a neonatal intensive care unit was similar between groups (4.2% (n = 21) vs 5.0% (n = 25); relative risk (RR), 0.85 (95% CI, 0.48-1.50); P = 0.57). In the AFI group, there were more cases of oligohydramnios (9.8% (n = 49) vs 2.2% (n = 11); RR, 4.51 (95% CI, 2.2-8.57); P < 0.01) and more cases of labor induction for oligohydramnios (12.7% (n = 33) vs 3.6% (n = 10); RR, 3.50 (95% CI, 1.76-6.96); P < 0.01) than in the SDP group. Moreover, an abnormal cardiotocography was seen more often in the AFI group than in the SDP group (32.3% (n = 161) vs 26.2% (n = 132); RR, 1.23 (95% CI, 1.02-1.50); P = 0.03). The other outcome measures were not significantly different between the two groups. CONCLUSIONS: Use of the AFI method increased the rate of diagnosis of oligohydramnios and labor induction for oligohydramnios without improving perinatal outcome. The SDP method is therefore the favorable method to estimate amniotic fluid volume, especially in a population with many low-risk pregnancies. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Sequential use of double-balloon catheter and oral misoprostol versus oral misoprostol alone for induction of labour at term (CRBplus trial): a multicentre, open-label randomised controlled trial.

OBJECTIVE: To evaluate the efficacy of inducing labour using a double-balloon catheter and oral misoprostol sequentially, in comparison with oral misoprostol alone. DESIGN: A multicentre randomised controlled trial. SETTING: Five hospitals in Germany. POPULATION: A total of 326 pregnant women with an unfavourable cervix undergoing labour induction at term. METHODS: Women were randomly assigned according to a computer-generated allocation sequence to sequential use of double-balloon catheter and oral misoprostol (study group) or oral misoprostol alone (control group). In the study group, the double-balloon catheter was used the first day before starting oral misoprostol the second day. MAIN OUTCOME MEASURES: The primary outcome measure was the induction-to-delivery interval, and a further outcome parameter was delivery within 48 hours. RESULTS: The median times for induction of labour until delivery were 32.4 hours in the study group and 22.5 hours in the control group (P = 0.004). This difference was not seen when evaluating according to parity (nulliparous, P = 0.19; parous, P = 0.06). The rate of vaginal delivery within 48 hours did not differ between both groups. The number of applications of misoprostol (two versus three, P < 0.001) and the dose of misoprostol used was lower in the study group (100 versus 200 µg, P < 0.001). In the study group, there were more Apgar scores of <7 at 5 minutes (8 versus 1, P = 0.04). CONCLUSIONS: The use of a double-balloon catheter on the first day, before starting oral misoprostol on the second day, did not improve the induction to delivery interval and the rate of delivery within 48 hours, in comparison with oral misoprostol alone.

[Impact of a Guideline for Management of Pregnancy beyond Term and its Influence on Clinical Routine]. / Einfluss der Leitlinie zum Vorgehen bei Terminüberschreitung auf den klinischen Alltag.

PURPOSE: Many international guidelines recommend induction of labour beyond 41 weeks to reduce perinatal morbidity and mortality. In 2010, a new German guideline with this recommendation was published. The aim of this study was to investigate whether this recommendation influenced clinical outcome. MATERIAL AND METHODS: All cases with induction of labour beyond 40 weeks in 2008, 2009, 2011 and 2012 were examined. Multiple pregnancy and Caesarean section in the case history were exclusion criteria. The years before publication of the new German guideline (2008 and 2009) were compared with those afterwards (2011 and 2012) with regard to several outcome parameters like rate of labour induction, efficacy of induction of labour and foetal outcome. RESULTS: After publication of the guideline there were more inductions of labour undertaken (300 [11.2%] vs. 472 [15.4%], p<0.0001) with less pregnancies beyond 42 weeks (9 [3%] vs. 5 [1%], p=0.0489). However, there was no difference concerning the efficacy of induction of labour, e. g., the ratio of Caesarean sections was not increased. There was no impairment of foetal outcome, in contrast, the ratio of postpartal admission to NICU was decreased (42 [14.2%] vs. 31 [6.7%], p=0.0006). CONCLUSION: The new recommendation of the German guideline to induce labour beyond 41 weeks leads to more cases with induction of labour without any negative impact on its efficacy or foetal outcome.

What are the limits of accuracy in fetal weight estimation with conventional biometry in two-dimensional ultrasound? A novel postpartum study.

OBJECTIVE: Commonly used formulae for fetal weight estimation, including combinations of several biometric parameters, lack accuracy despite efforts to improve them. This study aimed to investigate the limits of fetal weight estimation based on conventional biometric parameters on two-dimensional (2D) ultrasound by developing and evaluating new weight equations using postpartum biometric parameters. METHODS: This was a prospective multicenter study including 628 singleton pregnancies at term. Inclusion criteria were healthy newborns with no physical or chromosomal malformations. Postpartum measurement of head circumference, abdominal circumference and thigh length was performed. Six 'best-fit' formulae were derived using forward regression analysis in a formula-finding group (n = 419), and their accuracy was compared with birth weight in an evaluation group (n = 209) using percentage error, absolute percentage error, limits of agreement and the proportion of weight estimations falling within a discrepancy level of ± 10%. RESULTS: The new formulae showed no systematic error, with SD for the percentage error between 7.42 and 8.77 and no significant differences between median absolute percentage errors (4.84-5.71). They included 74.6-81.3% of neonates within a discrepancy level of 10%. With regard to the 95% limits of agreement, weight estimates were within a range of about ± 500 g. CONCLUSION: These results show that a good sonographic weight formula has the following features: no systematic error, an SD of about 7% and inclusion of 80% of cases within a discrepancy level of 10%. The study indicates that the current accuracy of fetal weight estimation with conventional biometric parameters by 2D ultrasound has reached its limits. Further improvement will probably only be achieved through new approaches in ultrasonography.

[Expectations of pregnant women on an ideal maternity hospital]. / Welche Erwartungen stellen Schwangere an eine ideale Entbindungsklinik?

PURPOSE: The aim of this study was to evaluate expectations of pregnant women on an ideal maternity hospital. MATERIAL AND METHODS: We prospectively performed a survey among 566 pregnant women with regard to their expectations on a perfect hospital for obstetrics. Data collection was accomplished in 3 obstetrical departments in Mannheim, Germany. The questionnaire contained 23 general questions about sociodemographic characteristics and 34 specific questions about the anticipated childbirth. Women who were less than 20 weeks pregnant and women who did not speak German fluently were excluded from this study. RESULTS: In our survey the possibility to get to know midwifes and doctors at information evenings and a guided delivery room tour were defined as very important factors by the interviewed women. Of particular importance was a continuous care by a single midwife and the physical attendance of a family member during childbirth. Furthermore, friendliness of the staff and medical care by paediatricians after childbirth were identified to be important. To some extent, a modern appearance of the ward was also a matter of importance. CONCLUSIONS: The medical treatment of mother and the newborn child and the friendliness of the staff have been identified as the most important factors with regard to the expectations of women on an ideal maternity hospital. In addition, a pleasant ambiance of the ward and regular visits by a lactation specialist were named as important.

[Massive increase of foetal abdominal circumference due to hereditary polycystic kidney disease]. / Massive fetale Bauchumfangszunahme bei hereditärer Zystennierenerkrankung.

Autosomal recessive polycystic kidney disease (ARPKD) is a rare condition with a poor prognosis. We report on a 30-year-old primagravid woman in the 34th) week of gestation who was admitted to our hospital. ARPKD of the foetus had been sonographically suspected since the 26th week of gestation. Ultrasound examination showed big polycystic kidneys on both sides. The non-consanguineous parents wanted a maximum therapy for the infant. Foetal digitalisation because of heart insufficiency and prophylactic lung maturation was started. In the further course, Doppler sonographic values worsened and a Caesarean section was performed in the 34th week of gestation at the demand of the parents and due to the expected problems in case of a vaginal delivery. The weight of the newborn was 3,780 g and the abdominal circumference was 50 cm. The newborn was intubated immediately after birth and artificial ventilation was performed. Extracorporeal membrane oxygenation was not possible due to the bad cardial condition. The boy died 16 h after delivery. The parents refused genetic examination and autopsy of the newborn. ARPKD is a severe disease that may have obstetric relevance, due to the massively increased abdominal circumference. Therefore, termination of pregnancy or preterm induction of labor should be considered in order to avoid Caesarean section. Additionally, early prenatal diagnosis with genetic analysis of PRKD1 in cases of suspected ARPKD can be helpful.

Stress reactivity in preschool-aged children: Evaluation of a social stress paradigm and investigation of the impact of prenatal maternal stress.

Prenatal maternal stress is an established risk factor for somatic and psychological health of the offspring. A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in offspring has been suggested as an important mechanism. However, the impact of prenatal stress on stress reactivity in preschool-aged children is not yet well understood. This is partly due to the fact that for this age group there is no stress test as well established as for older children and adults. In the present work a previously published stress test (Kryski et al., 2011) was evaluated in a large sample of 45-month-old children (n = 339). Furthermore, the relation between measures of prenatal maternal stress and cortisol reactivity was investigated. Prenatal stress was defined as psychopathology (self-report available for n = 339; expert-rating available for a subsample of n = 246) and perceived stress (n = 244) during pregnancy. The stress paradigm elicited significant increases in salivary cortisol 30 and 40 min after the test, and 60.8% of the children were classified as responders. Lower cortisol levels after the stress test were observed in the group of children with prenatal stress defined as maternal psychopathology (both self-reported and expert-rated). Maternal perceived stress as a continuous measure was not significantly associated with cortisol levels. However, when comparing children in the highest quartile of maternal perceived stress to all other children, significantly lower cortisol values were observed in the prenatally stressed group. The present study confirms the paradigm by Kryski et al. as an effective stress test for preschool-aged children. Moreover, it provides further evidence that prenatal stress impacts HPA axis reactivity. Future studies should target the timing, nature, and intensity of prenatal stressors and their effect on the stress response in offspring at different developmental stages.

Prenatal maternal stress is associated with lower cortisol and cortisone levels in the first morning urine of 45-month-old children.

Prenatal stress (PS) has been related to altered hypothalamic-pituitary-adrenal (HPA) axis activity later in life. So far, studies in children assessing HPA axis functioning have focused on salivary cortisol, reflecting daytime activity. The present work is part of a prospective study and aims to extend knowledge about the association between PS and HPA axis regulation in children. To do so, we investigated cortisol, cortisone, and the ratio cortisone/(cortisone + cortisol) in the first morning urine of 45-month-old children in relation to several measures of maternal stress during pregnancy. Urinary cortisol and cortisone were measured by online turbulent flow chromatography coupled with high performance liquid chromatography-tandem mass spectrometry. PS was defined as: perceived stress for aim 1 (Perceived Stress Scale; n = 280); presence of self-reported (n = 371) and expert-rated psychopathology for aim 2 (Mini International Neuropsychiatric Interview; n = 281); continuous measures of anxiety and depression for exploratory aim 3 (State-Trait Anxiety Inventory and Edinburgh Postnatal Depression Scale; n = 280). Aim 1: Perceived maternal PS showed negative associations with cortisol and cortisone levels. Aim 2: The presence of expert-rated maternal psychopathology was associated with reduced morning cortisone. Aim 3: Continuous measures of anxiety and depression showed negative associations with cortisol and cortisone levels. After correcting for multiple testing, perceived maternal PS (aim 1) and prenatal level of anxiety (aim 3) were significant predictors of children's urinary cortisol and cortisone in the morning (and, in the case of cortisone, also prenatal level of depression). The ratio cortisone/(cortisone + cortisol) as a global marker for the balance between the enzymes metabolizing cortisol to cortisone and vice versa (11ß-hydroxysteroid dehydrogenases type 1 and 2; 11ß-HSD1 and 2) was not associated with any measure of maternal PS (aims 1-3). The present study provides insight into possible programming effects of PS on nocturnal HPA axis activity and a proxy of 11ß-HSD in a large sample. The results suggest that the nocturnal rate of cortisol production is lower in children exposed to PS, but do not support the hypothesis of divergent 11ß-HSD activity.

Diminished post-rest potentiation of contractile force in human dilated cardiomyopathy. Functional evidence for alterations in intracellular Ca2+ handling.

Post-rest contractile behavior of isolated myocardium indicates the capacity of the sarcoplasmic reticulum (SR) to store and release Ca2+. We investigated post-rest behavior in isolated muscle strips from nonfailing (NF) and endstage failing (dilated cardiomyopathy [DCM]) human hearts. At a basal stimulation frequency of 1 Hz, contractile parameters of the first twitch after increasing rest intervals (2-240 s) were evaluated. In NF (n = 9), steady state twitch tension was 13.7 +/- 1.8 mN/mm2. With increasing rest intervals, post-rest twitch tension continuously increased to maximally 29.9 +/- 4.1 mN/mm2 after 120s (P < 0.05) and to 26.7 +/- 4.5 mN after 240 s rest. In DCM (n = 22), basal twitch tension was 10.0 +/- 1.5 mN/mm2 and increased to maximally 13.6 +/- 2.2 mN/mm2 after 20 s rest (P < 0.05). With longer rest intervals, however, post-rest twitch tension continuously declined (rest decay) to 4.7 +/- 1.0 mN/mm2 at 240 s (P < 0.05). The rest-dependent changes in twitch tension were associated with parallel changes in intracellular Ca2- transients in NF and DCM (aequorin method). The relation between rest-induced changes in twitch tension and aequorin light emission was similar in NF and DCM, indicating preserved Ca(2-)-responsiveness of the myofilaments. Ryanodine (1 microM) completely abolished post-rest potentiation. Increasing basal stimulation frequency (2 Hz) augmented post-rest potentiation, but did not prevent rest decay after longer rest intervals in DCM. The altered post-rest behavior in failing human myocardium indicates disturbed intracellular Ca2- handling involving altered function of the SR.

Comparison of Conservative and Surgical Therapy Concepts for Synechia of the Labia in Pre-Pubertal Girls.

Introduction: The aim of this study was to evaluate the primary and secondary therapeutic successes of different therapy schemes for the treatment of synechia of the labia in pre-pubertal girls. Materials and Methods: The treatment courses of 47 pre-pubertal girls who were treated between February 2007 and February 2013 in the special outpatient clinic for paediatric gynaecology of a department for gynaecology at a German university hospital and for whom information on the course of the disease was available for at least the six months following end of the treatment. 23 of these children were treated with a topical estriol therapy (treatment group A). For 24 of the girls a manual separation of the adhering labia minora was undertaken (treatment group B). Statistical evaluation was performed using the χ2 test, Fischer's exact test and the Mann-Whitney U test. Results: For 18 of the 23 (80 %) girls in treatment group A topical estriol therapy alone led to a resolution of the synechia. Five of these 23 children (20 %) required a secondary manual separation. All girls for whom treatment was not successful were under 5 years of age. For all 24 girls (100 %) of treatment group B the primary manual separation was performed with success. The recurrence rates after ≥ 6 months in cases with identical after-care did not differ between the two treatment groups (treatment group A: 34 %, treatment group B: 33 %, χ2 test: p = 0.853). 16 of the 17 recurrences occurred ≥ 3 months after the end of the therapy. Conclusion: Our results show that for children < 5 years of age a 4-week topical therapy with estriol is a promising therapy option for synechia of the labia that is less of a burden for the family situation. Especially for girls ≥ 5 years of age, primary therapy fails in up to 20 % of the cases. Primary manual separation represents a more effective therapeutic option. Irrespective of the treatment applied, a recurrence after ≥ 3 must be expected in one-third of the treated girls.

Brain metastases in breast cancer--an in vitro study to evaluate new systemic chemotherapeutic options.

BACKGROUND: Fifteen-30% of breast cancer patients develop central nervous system (CNS) metastases. The most potent drugs for the treatment of breast cancer like taxanes, anthracyclines and trastuzumab have limited efficacy for brain metastases. No standardized therapy has yet been established for this condition. Drugs with proven efficacy in the CNS and which are commonly used for primary brain tumors were applied. We evaluated the capacity of these drugs to inhibit breast tumor cell growth in vitro. MATERIALS AND METHODS: Twelve primary cell cultures of pulmonary/pleural metastases of breast cancer and 3 commercially available cell lines were used for non-radioactive cytotoxicity assays to evaluate the efficacy of 3 different concentrations of Topotecan, Cisplatin, Nimustine, Vincristine, Irinothecan, Caelyx (pegylated liposomal Doxorubicin) and Etoposide. RESULTS: Topotecan, Cisplatin, Caelyx and Vincristine showed significantly higher cytostatic activity in vitro than Irinotecan, Etoposide and Nimustine. With regard to the median cytotoxicity, the order of drugs in our assays was Topotecan, Cisplatin, Vincristine, Caelyx, Irinotecan, Etoposide and Nimustine. Nimustine showed almost no efficacy against breast cancer cells. CONCLUSION: Topotecan, Cisplatin, Vincristine and Caelyx seem to be suitable candidates for further clinical evaluation. The data and the "liposomal packaging" suggest that Caelyx might be effective in the CNS. Since pulmonary metastases are often associated with brain metastases, evaluatingprimary cell cultures from malignant pleural effusions could be a valuable approach for the testing of new cytostatic drugs for brain metastases.

Heat shock protein 27 is associated with decreased survival in node-negative breast cancer patients.

BACKGROUND: Heat shock protein 27 (hsp27) is a molecular chaperone which supports cells to keep their homeostasis under stressful conditions. It is associated with resistance to chemotherapeutics, radiation and hyperthermia. The aim of this retrospective study was to investigate the prognostic value of hsp27 for patients with node-negative breast cancer. MATERIALS AND METHODS: Paraffin sections of 191 patients were stained immunohistochemically with a monoclonal antibody against hsp27. Median follow-up was 177 months. The results were correlated with clinical and histopathological parameters using the Chi-square test. RESULTS: There was no significant correlation between hsp27 expression and standard histopathological features or the proliferation marker ki-67. Disease-free survival (DFS) was not altered for patients expressing hsp27-positive tumors, whereas overall survival (OS) [p=0. 02] and survival after first recurrence (SR) [p=0.01] were significantly decreased. CONCLUSION: The expression of hsp27 in primary breast cancers is associated with a short survival for node-negative patients.

Antigen-presenting cells in human endometrium during the menstrual cycle compared to early pregnancy.

OBJECTIVE: Human endometrium and early pregnancy decidua harbor a considerable and diverse population of antigen-presenting cells (APC). Changes in the number and distribution of macrophages and dendritic cells (DC) could point to a possible role of these immunocompetent cells in implantation and success of early pregnancy. METHODS: Uterine tissue was obtained from 22 women undergoing hysterectomy for bleeding disorders or dysmenorrhea and from 11 women undergoing legal abortion. Tissue was investigated with antibodies against CD14, CD68, CD83, DC-SIGN, Ki-67, and human leukocyte antigen (HLA)-DR using single and double immunohistochemical staining techniques. RESULTS: The number of CD14(+) cells was stable during all phases of the menstrual cycle and early pregnancy. In comparison to nonpregnant endometrium, DC-SIGN(+) cells showed a higher proliferation rate and were found associated in clusters with CD56(+) natural killer (NK) cells in early pregnancy. In the late secretory phase of the menstrual cycle, numbers of CD83(+) (P <.01) cells were significantly higher than in other endometrial phases and early pregnancy. HLA-DR(+) expression was significantly increased in early pregnancy but remained unchanged throughout the menstrual cycle. CONCLUSION: The presence of DC-SIGN(+) cells during the menstrual cycle and their proliferation in early pregnancy suggests an important role of these cells with regard to the balance between defense against pathogens and tolerance of the fetal allograft. Whether the increase of CD83(+) mature DC and CD68(+) macrophages in the late secretory phase is caused by hormonal stimuli and/or is due to changes of the cytokine/chemokine micromilieu remains to be investigated.

Clinical value of CYFRA 8/18 and TPS in the diagnosis and follow up of invasive breast cancer.

In a prospective study, we evaluated the diagnostic accuracy of CYFRA 8/18, TPS, CEA and CA 15-3 among 415 patients in various clinical situations of invasive breast cancer and 244 women with benign breast diseases. In comparison to TPS, the sensitivity of CYFRA 8/18 was slightly lower as well in local malignancy (25% vs. 30%) as in metastatic cancer (54% vs. 57%), but in follow up care the rate of false positive results of TPA (> or = 25%) seems to be higher than that of CYFRA 8/18 (> or = 17%). In conclusion, the clinical value of CYFRA 8/18 and TPA appears to be similar.

CASA and Ca 125 in diagnosis and follow-up of advanced ovarian cancer.

BACKGROUND: CA 125 is the most important tumor marker in ovarian cancer. Due to its low specificity and the fact that some ovarian malignancies do not produce considerable amounts of CA 125 a combination with the Cancer Associated Serum Antigen (CASA) may reflect more accurately the clinical situation. MATERIALS AND METHODS: CA 125 and CASA determination was performed in sera of 78 patients with advanced ovarian cancer pre- and postoperatively, monthly during chemotherapy and during follow-up care. The cut-off values for CASA were 4 U/ml, for CA 125 35 U/ml and 65 U/ml, respectively. RESULTS: In the detection of advanced ovarian cancer a combination of both tumor markers was superior to the use of either CASA or CA 125 alone. In the follow-up situation CA 125 with the 35 U/ml cut-off showed the highest sensitivity. Both markers had similar prognostic relevance when marker levels three months after surgery were used. CONCLUSION: CA 125 and CASA have similar characteristics in preoperative diagnosis and postoperative follow-up. In clinical situations with inconclusive or negative CA 125 serum values CASA is helpful to improve management of patients with advanced ovarian cancer.

Predictive value of CEA and CA 15-3 in the follow up of invasive breast cancer.

BACKGROUND: The clinical usefulness of tumor markers in the follow-up care of invasive breast cancer is controversial. METHODS: In 1228 serum samples of 664 women with history of breast cancer, the diagnostic accuracy and predictive power of CEA and CA 15-3 for the detection of disease relapse was determined prospectively by analyzing the clinical course for at least 6 months after the measurement of the tumor markers in 1994. RESULTS: A total of 76 patients relapsed during the period of study. The diagnostic accuracy was 83% for CEA and 88% for CA 15-3. CEA and CA 15-3 had a positive predictive value of 27% and 47% as well as a negative prediction of 91% and 93%, respectively. CONCLUSIONS: The low positive predictive value and sensitivity of these tumor markers clearly limit their clinical utility. Therefore, the effectiveness of routine determinations during the follow-up seems questionable.

Correlation of the EGF-receptor with cell kinetic and classical prognostic factors in breast cancer.

SPECIFIC OBJECTIVE: The Epidermal Growth Factor Receptor (EGFR) is a specific cell membrane receptor that shows homology to the product of the oncogene c-erbB2 in human breast cancer. Growth factors bound to the EGFR are able to stimulate the growth of tumor cells in an autocrine or paracrine manner. Our objective was to examine whether there is a relationship between EGFR, cell kinetic prognostic factors (ploidy, proliferation-antigen Ki67) and classical prognostic factors (hormone receptors, menopausal status, nodal status) in breast cancer. METHODS: EGFR was assayed in tumor tissue of 55 patients with breast cancer using an ELISA, the ploidy-status was evaluated by image analysis and Ki67 was determined by immune histochemistry. Estrogen- (ER) and Progesterone-Receptor (PR)-concentrations were quantified using a radioligand assay. RESULTS: There was a significant positive correlation between the EGFR and the cell kinetic prognostic factors: EGFR positive tumors were significantly-more often aneuploid and Ki67-positive. In addition there was an inverse association between EGFR- and ER-concentration, but no association between EGFR and PR. The EGFR did not correlate with the nodal and the menopausal status. CONCLUSIONS: Our study revealed associations between EGFR, ER, Ki67 and ploidy. Whether these correlations can help to predict the course of disease, providing further information in addition to the conventional factors (nodal status, steroid hormone receptors etc.) has to be investigated by several years of clinical follow up.

Evaluation of tartrate-resistant acid phosphatase (TRAP) 5b as serum marker of bone metastases in human breast cancer.

BACKGROUND: The osteoclast-specific active TRAP 5b isoform is detectable in serum and claimed to be a specific marker of bone resorption. The present study was undertaken to evaluate the usefulness of TRAP 5b as a serum marker of bone resorption in breast cancer patients with bone metastases. MATERIALS AND METHODS: TRAP 5b serum levels were measured in 192 samples from patients with breast cancer with and without bone metastases and in 53 healthy pre- and postmenopausal women using the enzyme immunoassay Bone-TRAP. RESULTS: Serum levels of TRAP 5b were significantly higher in patients with breast cancer and clinical signs of bone metastases before therapy than in healthy women. There was also a significant difference between patients with bone metastases before and during bisphosphonate therapy, indicating a reduction of bone alteration under this treatment. The subgroup with progression of bone metastases under bisphosphonate therapy showed the highest difference in TRAP 5b concentrations compared to patients with stable disease. CONCLUSION: Serum TRAP 5b levels are elevated in patients with bone metastases and breast cancer. The TRAP 5b levels decline under bisphosphonate therapy when no progression is detectable. When progress of the bone metastases occurs, TRAP 5b levels rise again. Therefore, active TRAP 5b seems to be a useful serum marker for bone metastases in breast cancer patients, especially to detect progressive disease under bisphosphonate treatment. Further studies with larger numbers of patients are required to confirm these data.

The correlation of c-erbB-2 oncoprotein and established prognostic factors in human breast cancer.

BACKGROUND: The c-erbB-2 (HER2/neu) receptor is a transmembrane phosphoglycoprotein associated with multiple signal transduction pathways. Its overexpression in breast cancer tissue has been correlated with poor prognosis. We report preliminary data of an ongoing study in invasive breast cancer patients exploring c-erbB-2 protein overexpression in relation to established tumor characteristics of prognostic value. MATERIALS AND METHODS: In primary breast carcinoma samples from 115 women undergoing surgery in our department in 1999, a polyclonal rabbit antibody to human c-erbB-2 oncoprotein was used for immunohistochemical assessment of the c-erbB-2 expression in formalin-fixed paraffin-embedded material. The data were statistically correlated with classical histopathological parameters. RESULTS: In the studied collective of mainly postmenopausal women (75%) with a high rate of early stage breast cancer (88% pT1 + 2), there was no significant relation between c-erbB-2 overexpression, classified as positive in 42% of the samples, and lymph node involvement, tumor size and grade, or hormone receptor status. CONCLUSION: Using the presented highly sensitive method, no association between c-erbB-2 expression and established prognostic factors was found. These data are in line with reports that the value of HER2/neu determination is not fully clarified for the preadjuvant evaluation of newly diagnosed breast cancer patients.