[Case Report on Treatment of Metastatic Breast Cancer with Trastuzumab during Pregnancy]. / Fallbericht einer Trastuzumab-Therapie während der Schwangerschaft bei metastasiertem Mammakarzinom.

The increasing number of pregnant breast cancer patients calls for a therapy that is as efficient as possible. After 10 years of collecting data on pregnant breast cancer patients in the German Breast Group (GBG), proposals for diagnostic measures and therapy regarding this special situation have been developed on the basis of 500 observed cases. Chemotherapy is regarded as safe from the 14(th) week of gestation on, but it is strongly advised not to use trastuzumab. Adverse outcomes for the newborn were predominantly observed in cases of early preterms. In our department, a 29-year-old second gravida with metastatic breast cancer first diagnosed 7 years ago continued to receive trastuzumab treatment at her express request after detailed information and advice. Trastuzumab treatment had been started 1.5 years before the pregnancy after surgical removal of a lymph node metastasis. After 7 intravenous administrations at intervals of 3 weeks, an oligohydramnios occurred in the 24(th) week of pregnancy. For this reason, trastuzumab treatment was interrupted for 7 weeks, during which time the quantity of amniotic fluid returned to a normal level. As the 8(th) administration of trastuzumab led to a renewed oligohydramnios, the trastuzumab treatment was suspended until birth. The quantity of amniotic fluid having recovered to normal, labour was induced after 36 weeks of pregnancy, followed by a Caesarian section because of prolonged labour. The newborn boy showed no sign of respiratory or renal dysfunction and has developed normally, having at present reached the age of 3 years. From the few reported cases of pregnancies with trastuzumab therapy, it seems that an occurring oligohydramnios is the typical complication with the problem of life-threatening RDS after birth. Probably the reduction of amniotic fluid can be reversed by interrupting the trastuzumab therapy, as we observed in our case.

[Pneumomediastinum related to the second stage of labour - a report on 2 cases]. / Mediastinal- und Subkutan-Emphysem in Folge einer Vaginalgeburt - ein Bericht über 2 Fälle.

We report on 2 primigravidae developing pneumomediastinum and subcutaneous emphysema associated with the second stage of labor. Both of the newborns had a comparatively high birth-weight (3,855 g and 4,245 g, respectively). In the first case, the patient felt a sudden chest pain during expulsion followed by dyspnea and swelling of the face. The birth was terminated by vacuum extraction. In the second case, a mild shoulder dystocia occurred, which could be resolved by McRoberts maneuver. The patient exhibited a swollen face and shortness of breath on the first postpartum day. Physical examination revealed crackly skin over the lower face, both sides of the neck and the front of the chest. In both cases, CT scan of the chest revealed pneumomediastinum and a subcutaneous emphysema of the upper thorax, however without showing a pneumothorax. The first patient underwent bronchoscopy and esophagogastroduodenoscopy; there were no abnormalities detected. The pneumomediastinum and subcutaneous emphysema gradually diminished spontaneously in both cases. Appropriate pain management and empirical antibiotics were applied. Pneumomediastinum during labor and birth, typically with subcutaneous emphysema in the face and neck, is a rare condition, but there are reported cases in the literature. Based on the limited available evidence, it seems to have a benign, self-limiting course. A conservative management appears -appropriate and sufficient.

[Ultrasonographic clarification of adnexal findings]. / Sonographische Abklärung eines Adnexbefundes.

The most important diagnostic test for clarification of an adnexal mass is ultrasonographic evaluation. The prognostic value of an ultrasonographic examination is higher in combination with the patient history and clinical findings. In order to achieve high diagnostic accuracy certain requirements are mandatory. Firstly a high level of expertise, meticulousness and patience of the examiner is crucial. Secondly the use of a high-end ultrasound machine is essential. Thirdly a thorough evaluation and interpretation of sonomorphologic findings are necessary. Furthermore, these skills have to be trained continuously. This is fundamental for subjective, sonographic pattern recognition and the successful use of tumor scores resulting in a correct classification of adnexal tumors. Most adnexal tumors (approximately 75%) can be correctly (sensitivity 95% and specificity 91%) classified as benign or malignant using a set of simple rules. Tumors which cannot be classified (approximately 25%) can be differentiated by ultrasound examination by an expert examiner on the basis of subjective evaluation in about 90% of cases.

[Fractures in neonates as a result of birth trauma caused by caesarean section]. / Geburtstraumatische Frakturen nach Kaiserschnitt.

BACKGROUND: The occurrence of 4 bone fractures associated with birth by Caesarean section (CS) prompted us to examine the incidence and predisposing factors of bone injuries sustained during birth. CASE REPORT AND METHOD: The 4 cases with fractures were evaluated retrospectively and discussed in combination with a short review of the literature. CONCLUSIONS: With the increasing number of Caesarean sections the incidence of birth trauma has decreased. Nevertheless, when performing a CS there is still a risk of serious trauma to the neonate, including bone fractures. A Caesarean section for breech presentation constitutes a predisposition for femoral fractures. When diagnosed early and treated properly, the prognosis for these fractures is good without sequelae and one can expect a satisfactory clinical outcome for the child. We suggest that the possibility of this complication be mentioned when counselling the mother and getting informed consent.

Treatment of very preterm preeclampsia via heparin-mediated extracorporeal LDL-precipitation (H.E.L.P.) apheresis: The Freiburg preeclampsia H.E.L.P.-Apheresis study.

OBJECTIVE: Soluble Fms-like tyrosine kinase-1 (sFlt-1) is thought to be causative in the pathogenesis of preeclampsia (PE) and specific removal of sFlt-1 via dextran sulfate cellulose (DSC)-apheresis was suggested as cure to allow prolongation of pregnancy in preterm PE. However, in addition a deranged lipoprotein metabolism may impact endothelial and placental function in PE. Lipoprotein-apheresis by heparin-mediated extracorporeal LDL-precipitation (H.E.L.P.) was previously applied and has been shown to alleviate symptoms in PE. This clinical trial reevaluates the clinical efficacy of H.E.L.P.-apheresis in PE considering sFlt-1. STUDY DESIGN: Open pilot study assessing the prolongation by H.E.L.P.-apheresis in 6 women (30-41 years) with very preterm PE (24+4 to 27+0 gestational weeks (GW)) (NCT01967355) compared to a historic control-group matched for GW at admission (<28 GW; n = 6). Clinical outcome of mothers and babies, and pre- and post H.E.L.P.-apheresis levels of sFlt-1 and PlGF were monitored. MAIN OUTCOME MEASURES: In apheresis patients (2-6 treatments), average time from admission to birth was 15.0 days (6.3 days in controls; p = 0.027). Lung maturation was induced in all treated cases, and all children were released in healthy condition. Apheresis reduced triglycerides and LDL-cholesterol by more than 40%. Although H.E.L.P.-apheresis induced a transient peak baseline levels did not change and rather stabilized sFlt-1 levels at pre-apheresis levels throughout treatments, with sFlt-1/PLGF ratio remaining unaffected. CONCLUSIONS: H.E.L.P.-apheresis proved again to be safe and prolongs pregnancies in PE. However, without changing sFlt-1 levels below baseline lowering lipids or other yet undefined factors appear to be of more relevance than reducing sFlt-1.

Screening of gestational diabetes mellitus in early pregnancy by oral glucose tolerance test and glycosylated fibronectin: study protocol for an international, prospective, multicentre cohort trial.

INTRODUCTION: As the accurate diagnosis and treatment of gestational diabetes mellitus (GDM) is of increasing importance; new diagnostic approaches for the assessment of GDM in early pregnancy were recently suggested. We evaluate the diagnostic power of an 'early' oral glucose tolerance test (OGTT) 75 g and glycosylated fibronectin (glyFn) for GDM screening in a normal cohort. METHODS AND ANALYSIS: In a prospective cohort study, 748 singleton pregnancies are recruited in 6 centres in Switzerland, Austria and Germany. Women are screened for pre-existing diabetes mellitus and GDM by an 'early' OGTT 75 g and/or the new biomarker, glyFn, at 12-15 weeks of gestation. Different screening strategies are compared to evaluate the impact on detection of GDM by an OGTT 75 g at 24-28 weeks of gestation as recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG). A new screening algorithm is created by using multivariable risk estimation based on 'early' OGTT 75 g and/or glyFn results, incorporating maternal risk factors. Recruitment began in May 2014. ETHICS AND DISSEMINATION: This study received ethical approval from the ethics committees in Basel, Zurich, Vienna, Salzburg and Freiburg. It was registered under http://www.ClinicalTrials.gov (NCT02035059) on 12 January 2014. Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02035059.

Diagnostic formula for the differentiation of adnexal tumors by transvaginal sonography.

OBJECTIVE: To create a strategy for sonographic differentiation of benign and malignant adnexal tumors in premenopausal and postmenopausal patients. METHODS: Multiple sonomorphologic criteria were analyzed prospectively in 754 tumors. Four hundred were found in premenopausal and 354 in postmenopausal women. In a logistic regression model, relevant criteria were selected, and a diagnostic formula for tumor differentiation was derived. RESULTS: There were 165 malignant tumors, of which 37 (9.2%) were found in premenopausal and 128 (36.2%) in postmenopausal women. In both groups, the criteria of solid phase and ascites were the most significant. Further important diagnostic criteria were structure and tumor size in premenopausal women and cyst architecture and tumor surface in postmenopausal women. These results allowed an estimation of the probability of malignancy. Using a cutoff point of 10% for the probability to classify tumors as malignant, the sensitivity and specificity in premenopausal patients were 86.5% and 92.6%, respectively, with an accuracy of 92%. In postmenopausal women, the sensitivity, specificity, and accuracy were 93%, 82.7%, and 86.6%, respectively. Assuming a prevalence as given in the study, the positive and negative predictive values were 54.4% and 98.5% in premenopausal and 75.3% and 95.4% in postmenopausal women. CONCLUSIONS: With four binary criteria, a useful diagnostic formula for tumor differentiation was obtained. However, estimates for sensitivity, specificity, and accuracy may be too optimistic because they were derived from the same data that were already used for model selection.

Color Doppler flow criteria of breast lesions.

Color Doppler technique has been available for several years. The sensitivity of the equipment has improved and allows for assessment of tumor vascularity. We investigated multiple parameters in 258 patients, with 176 benign and 82 malignant lesions to define characteristic flow criteria. Median (25-75% quartiles) and p-values are given for benign vs. malignant lesions. Number of tumor vessels: 2 (1-2) vs. 8 (5-14), p < 0.0001; mean peak systolic flow velocity: 11.1 cm/s (6.4-14.9) vs. 18.8 cm/s (13.7-25.1), p < 0.0001; maximum flow velocity: 12.5 cm/s (6.7-18) vs. 32.5 cm/s (22.5-47.3), p < 0.0001; sum of all systolic flow velocities: 18.9 cm/s (7-34.2) vs. 147 cm/s (71.3-266.7), p < 0.0001; minimum systolic flow velocity: 8.9 cm/s (5.4-12.1) vs. 9 cm/s (6.3-11.3), p > 0.05; average resistance index (RI): 0.68 (0.58-0.72) vs. 0.75 (0.67-0.81), p > 0.05; maximum RI: 0.71 (0.65-0.78) vs. 0.88 (0.78-0.99), p < 0.0001; minimum RI: 0.64 (0.57-0.68) vs. 0.64 (0.53-0.71), p > 0.05; average A/B ratio: 3.1 (2.7-3.7) vs. 4.3 (3.2-7.7), p < 0.0001; maximum A/B ratio: 3.4 (2.9-4.6) vs. 8.4 (4.5-9.9), p < 0.0001; minimum A/B ratio: 2.8 (2.3-3.2) vs. 2.9 (2.2-3.5), p > 0.05. The data analysis shows that flow resistance in malignancies is increased. This is in contrast to gynecological malignancies, where an increased diastolic flow indicates that flow resistance is decreased.

Differentiation of benign and malignant breast tumors by logistic regression and a classification tree using Doppler flow signals.

In breast examinations with Doppler, an increased flow is found in malignant tumors. With the relatively new color Doppler, we measured different flow values in 133 cancer patients and in 325 women with benign disease. These measurements were used to develop diagnostic rules. For the highly correlated flow values, we used a stepwise procedure to select a final logistic regression model and a tree-based approach, which is a different way of modeling. With both approaches we developed simple diagnostic rules of which the sensitivity and the specificity exceeded 90%. There are no differences between the two approaches concerning discriminative ability. As complex statistical modeling leads to an overoptimism in the assessment of the error rates, we applied sensitivity analysis, investigated the stability of the selected logistic regression model, and estimated the magnitude of the overoptimism of the diagnostic rules with resampling methods. The results indicate that the estimates of sensitivity and specificity are probably close to realistic values for a clinical setting.

Doppler measurement of breast vascularity in women under pharmacologic treatment of benign breast disease.

Breast vascularization was measured with an 8-MHz continuous wave Doppler pencil probe. Flow values were low in asymptomatic women and high in patients with severe pain or dysplastic changes. Mild treatment with a plant extract produced only a small decrease in breast vascularization. Treatment with norethisterone acetate showed a dose-dependent decrease in blood flow. A good response was seen with a dosage of 5 mg/d, and a dramatic decrease was seen when 10 mg/d was taken. These results showed a good correlation with the patients' symptoms.

[Fetal renal failure after intrauterine exposure to inhibitors of the renin-angiotensin system]. / Fetale Niereninsuffizienz bei Therapie mit Hemmstoffen des Renin-Angiotensin-Systems in der Schwangerschaft.

UNLABELLED: HISTORY AND AIM: A 36-year-old woman (primigravida, nullipara) at 25 + 3 weeks of gestation and a 27-year-old (primigravida, nullipara) at 22 + 7 weeks of gestation presented with oligo-/anhydramnios at our department of obstetrics. Both patients suffered from diabetes type 1 and 2, respectively, complicated by diabetic nephropathy, renal hypertension and retinopathy. The first woman had received an AT1 receptor antagonist and a beta blocker, the other one an ACE inhibitor and a beta blocker. At initial clinical examination both patients were in a good general state of health. Respiration, pulse and blood pressure were within normal limits. INVESTIGATIONS: Sonography showed oligy-/anhydramnion with enlarged echogenic kidneys of both fetuses. Having ruled out premature rupture of the membranes the reduced amount of amniotic fluid was interpreted as a consequence of the antihypertensive medication. TREATMENT AND COURSE: The medication was changed to methyldopa which resulted in an adequate and moderate increase of amniotic fluid in both patients. At post partum examination renal failure was confirmed in both infants. The first infant, now a boy at the age of two years, still suffers from chronic renal failure, needing antihypertensive medication with an ACE blocker. Follow-up of the second baby has so far shown normal growth of the kidneys and normotensive blood pressure. CONCLUSION: When planning a pregnancy, a preexisting hypertension should be treated with either methyldopa (1st choice) or a beta blocker as a second choice (e. g. Metoprolol). In patients who are treated with ACE blockers or AT1 antagonists, medication should be changed as soon as the pregnancy is ascertained.

Factors Associated with the Duration of Breastfeeding in the Freiburg Birth Collective, Germany (FreiStill).

Purpose: The health benefits of breastfeeding for both infants and mothers are well-documented. The aim of this study was to clarify factors associated with successful breastfeeding. Methods: We performed a prospective, multi-centre cohort study of 443 mothers in person using a standardised questionnaire on postpartum day 1. Women who had started to breast-feed were interviewed by telephone after 3, 6 and 12 months. A statistical analysis was performed using the SAS system. Results: 92 % of women (409/443) were initially breastfeeding. After three months the rate decreased to 74 %, after six months to 61 % and after 12 months to 28 %, respectively. Bivariate analysis revealed a significant positive association with the following factors: maternal age > 35 years, higher educational level, intention to breastfeed on postpartum day one, high motivation after three months, partner's support of the decision to breastfeed, satisfaction with the care provided in the maternity clinic, a positive breastfeeding experience and follow-up care by a midwife. Elective caesarean delivery, the use of breastfeeding aids, formula supplementation early on and the mother's concern about the amount of milk correlated negatively. Following a multivariate logistic regression analysis, four factors were correlated with having a positive influence on duration of breastfeeding: higher educational level, satisfaction with the care provided within the maternity clinic, follow-up care by a midwife, and a positive current experience of breastfeeding. Conclusion: Our data demonstrate certain factors successfully influence breastfeeding. Competent care in the maternity clinic, postpartum care by a midwife and a positive experience with breastfeeding increase the rate of breastfeeding and thus have a positive impact on the health of mother and newborn.

Three-dimensional ultrasound for the assessment of breast lesions.

OBJECTIVE: To evaluate the diagnostic accuracy of three-dimensional (3D) ultrasound in comparison with conventional two-dimensional (2D) ultrasound in the characterization of breast lesions. METHODS: The digitally stored 2D ultrasound images and the corresponding 3D scans of 100 breast lesions (57 malignant, 43 benign) that had been morphologically classified as solid tumors, were independently analyzed by six investigators. Ten 2D and 13 3D ultrasound characteristics were determined. Lesion characterization was classified on a four-point scale and a logistic regression model was used to analyze the data. A receiver-operating characteristics curve (ROC) analysis was performed to determine the diagnostic performance of 2D and 3D ultrasound, respectively. RESULTS: Ultrasound criteria showed major differences between 2D and 3D ultrasound. Logistic regression revealed the retraction phenomenon in the coronal plane of the 3D ultrasound scan to be a significant and independent factor for lesion characterization. The characteristics determined on the conventional planes of 3D ultrasound differed from those determined on the 2D ultrasound images. The diagnostic accuracy of 2D and 3D ultrasound in the ROC analysis was almost identical (area under the curve 0.846 and 0.851, respectively). CONCLUSIONS: Ultrasound features on 3D ultrasound differ significantly from those on 2D ultrasound. However, the diagnostic accuracy of both methods is almost identical. 3D ultrasound as an adjunct to conventional 2D ultrasound should be evaluated in larger trials to determine its clinical value in breast imaging.

[Use of gonadotropin releasing hormone analogs in Marcumar-treated patients for contraception and prevention of life-threatening ovulation hemorrhages]. / Einsatz von Gn-RH-Analoga bei markumarisierten Patientinnen zur Antikonzeption und Prophylaxe von lebensbedrohlichen Ovulationsblutungen.

Five severe cases of intra-abdominal gynaecological haemorrhage (four haemorrhages from corpora lutea haemorrhagica and one haemorrhage of the endometritis genitalis externa) are described in relation to prolonged marcumar therapy. The problem of contraception in patients under marcumar therapy is highlighted and the possibility is discussed of prevention of ovulation and cardio-vascularly neutral treatment, to achieve contraception as well as avoidance of haemorrhage at ovulation with the Gn-RH analogue Buserelin.

[Prolongation of premature multiple pregnancy after abortion of one or more fetuses]. / Prolongation unreifer Mehrlingsschwangerschaften nach Abort eines oder mehrerer Feten.

In four cases of one twin pregnancy and three triplet pregnancies, efforts were made to prolong the pregnancy after the death of one foetus between 15th and 26th weeks of gestation. Two patients had a history of spontaneous abortion, three patients had undergone infertility treatment. In a further three cases the membranes ruptured prematurely in association with severe disturbance of the vaginal flora. Treatment consisted of rest in bed, sedation, and administration of magnesium and antibiotics. Neither cervical cerclage nor general IV tocolysis were performed. Although the pregnancies could be prolonged for 4, 22, 28, and 76 days, they all terminated before the 27th week, mainly due to ascending infection. Of the 11 children, two survived with no morbidity, two children (B and C of the third triplet pregnancy), died 2 and 19 days after delivery, respectively, and seven were stillborn. A comparison with prolongations of twelve twin and four triplet pregnancies reported in the literature, reveals the various concepts for treatment. After infection has been ruled out and the parents have been fully informed, efforts could be made to prolong the multiple pregnancy after the death of one foetus until the surviving child is viable. This requires intensive supervision.

[Ultrasound biometry of the fetal heart]. / Sonographische Biometrie des fetalen Herzens.

We report on biometric measurements of the fetal heart with the TM-technique; these measurements were carried out between the 20th and 40th gestational week. The right and left endsystolic atrial and ventricular diameters were, measured, as well as the diameters of the large vessels, i.e. aorta and pulmonary artery; finally, the septal thickness was determined. Our measurements show a linear progression of the diameters in question, the right-left ratio of the atria and ventricles was close to one, so was the ratio between aorta and pulmonary artery. Our results are compared, as far as possible, to the literature.

Classification of adnexal tumors by transvaginal color Doppler.

The purpose was to evaluate the validity of transvaginal color Doppler sonography for differentiating between benign and malignant ovarian tumors. Color Doppler and Duplex measurements were obtained in 212 (144 benign, 68 malignant) ovarian and tubarian tumors preoperatively. One hundred and thirty-one patients were postmenopausal and 81 premenopausal. An ATL UM9/HDI was used. The following criteria were analyzed: minimum and mean resistance index and pulsatility index, number and distribution of tumor arteries, diastolic notch, and the maximum, minimum, mean, and sum of all peak systolic, maximum enddiastolic, and time-average maximum velocities. Most criteria showed highly significant differences between benign and malignant tumors with variable overlaps. RImin gives a sensitivity of 80%, specificity of 69%, and accuracy of 75% for postmenopausal patients and 80, 59, and 67% for pre- and postmenopausal patients, respectively. PImin gives equivalent results. The number of tumor arteries and the maximum flow velocities increase the accuracy. The summation of all flow velocities gives the best result with a sensitivity of 93%, specificity of 85%, and accuracy of 87% for postmenopausal and 91, 76, and 80% for pre- and postmenopausal tumors, respectively. Flow data show no relevant differences between low malignant potential tumors and ovarian carcinomas. Serous cystadenomas and benign teratomas show higher differences than mucinous cystadenomas, functional cysts, and endometriomas in comparison to malignancies. A separate analysis of pre- and postmenopausal tumors is important. Differentiation seemed better for post- than for premenopausal tumors. The four flow criteria (RImin, number of tumor arteries, and maximum and sum of all peak systolic velocities) seemed appropriate for tumor differentiation. However, this study confirms that a single measurement is not sufficient to differentiate ovarian lesions. Measurements of flow velocities (e.g., maximum and sum of all peak systolic velocities) are superior compared with RImin and PImin.

[Sonographic biometry of fetal organs]. / Sonographische Biometrie fetaler Organe.

Over a period of 18 months measurements of fetal Organs (cornu anterius of the lateral ventricle, medium diameter of the four-chamber-view of the heart, transverse diameter of lungs, stomach, gall bladder, colon and urinary bladder) were carried out in a population of 223 normal pregnancies. The measurements were correlated to the age of pregnancy and sonographic growth parameters (biparietal diameter--BPD, mean cephalic diameter--MCD, mean abdominal diameter--MAD). The results show different growth velocities of the particular organs, obviously depending on physiological function. The variability is increasing with fetal growth. We found no fundamental difference as far as correlation of organ measurements to age of pregnancy, to BPD, MCD or MAD. In summary the imaging and biometries of the fetal organs appear to be possible in relatively little time and such is a valuable method for the detection of fetal anomalies.

[Does color Doppler complement breast examination?]. / Ergänzt der Farbdoppler die Mammadiagnostik?

Improvements in breast cancer detection are underway with work being done on different imaging techniques and the assessment of abnormal vascularity. In an earlier study we used a 10 MHz CW Doppler pencil probe. In palpable carcinomas 94% had shown abnormal vascularity. However, in nonpalpable lesions, this method did not allow flow detection in combination with imaging. Recent developments in color flow mapping allow detection of small tumor vessels, which are invisible on B-mode ultrasound. Registration of vessels simultaneously to B-mode imaging allows this method to be used for nonpalpable lesions. The sensitivity of diverse Doppler instruments shows remarkable differences. This makes uniform evaluation of the method difficult. We examined 94 symptomatic women using different equipment. In 9 of 32 carcinomas no Doppler signals were found. However, CW Doppler showed low vascularity in these 9 false-negative cases. However, the variation of vascularity in malignancies does not yet allow routine application of this method and needs further scientific evaluation.