Universitätsklinik für Frauenheilkunde und Geburtshilfe

OBJECTIVES: Few data exist for counseling and perinatal management of women after an antenatal diagnosis of early-onset fetal growth restriction. Yet, the consequences of preterm delivery and its attendant morbidity for both mother and baby are far reaching. The objective of this study was to describe perinatal morbidity and mortality following early-onset fetal growth restriction based on time of antenatal diagnosis and delivery. METHODS: We report cohort outcomes for a prospective multicenter randomized management study of fetal growth restriction (Trial of Randomized Umbilical and Fetal Flow in Europe (TRUFFLE)) performed in 20 European perinatal centers between 2005 and 2010. Women with a singleton fetus at 26-32 weeks of gestation, with abdominal circumference < 10(th) percentile and umbilical artery Doppler pulsatility index > 95(th) percentile, were recruited. The main outcome measure was a composite of fetal or neonatal death or severe morbidity: survival to discharge with severe brain injury, bronchopulmonary dysplasia, proven neonatal sepsis or necrotizing enterocolitis. RESULTS: Five-hundred and three of 542 eligible women formed the study group. Mean ± SD gestational age at diagnosis was 29 ± 1.6 weeks and mean ± SD estimated fetal weight was 881 ± 217 g; 12 (2.4%) babies died in utero. Gestational age at delivery was 30.7 ± 2.3 weeks, and birth weight was 1013 ± 321 g. Overall, 81% of deliveries were indicated by fetal condition and 97% were by Cesarean section. Of 491 liveborn babies, outcomes were available for 490 amongst whom there were 27 (5.5%) deaths and 118 (24%) babies suffered severe morbidity. These babies were smaller at birth (867 ± 251 g) and born earlier (29.6 ± 2.0 weeks). Death and severe morbidity were significantly related to gestational age, both at study entry and delivery and also with the presence of maternal hypertensive morbidity. The median time to delivery was 13 days for women without hypertension, 8 days for those with gestational hypertension, 4 days for pre-eclampsia and 3 days for HELLP syndrome. CONCLUSIONS: Fetal outcome in this study was better than expected from contemporary reports: perinatal death was uncommon (8%) and 70% survived without severe neonatal morbidity. The intervals to delivery, death and severe morbidity were related to the presence and severity of maternal hypertensive conditions.

BACKGROUND AND OBJECTIVE: There is no valid method in the German literature for assessing postpartum depressive disorders. This study was undertaken to translate into German, validate and test the reliability of the Edinburgh postnatal depression scale (EPDS). PATIENTS AND METHODS: Randomly selected women after childbirth (n = 110) underwent (on the fourth postpartum day) a semistructured interview after first having answered the translated EPDS questionnaire. The diagnosis of depressive disorder was made according to the the criteria for psychological disorders in the ICD-10. For validation the results of the EPDS were compared with the clinical diagnosis of depression. The calculation of sensitivity, specificity and positive prognostic value was related to the respective EPDS results. In addition the EPDS data were analyses as to their reliability. RESULTS: The average age of the tested women was 28.6 years; 72% were married and 45% were primiparae. For an EPDS total score threshold value of 9.5 the sensitivity was 0.96, the specificity 1.0, and a positive prognostic value of 1.0. In the reliability analysis for EPDS the Guttmann split-half reliability was 0.82 and the alpha-coefficient 0.81. CONCLUSIONS: The German version of the EPDS with ten questions is an "application friendly" as well as proven to be a valid and reliable method for supporting the diagnosis of postpartum depressive disorder. It is suitable for both clinical and research use.

The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) is a scientific organization that encourages sound clinical practice, teaching and research related to diagnostic imaging in women's healthcare. The ISUOG Clinical Standards Committee (CSC) has a remit to develop Practice Guidelines and Consensus Statements as educational recommendations that provide healthcare practitioners with a consensus-based approach for diagnostic imaging. They are intended to reflect what is considered by ISUOG to be the best practice at the time at which they are issued. Although ISUOG has made every effort to ensure that Guidelines are accurate when issued, neither the Society nor any of its employees or members accepts any liability for the consequences of any inaccurate or misleading data, opinions or statements issued by the CSC. They are not intended to establish a legal standard of care because interpretation of the evidence that underpins the Guidelines may be influenced by individual circumstances and available resources. Approved Guidelines can be distributed freely with the permission of ISUOG (info@isuog.org). This document is a Practice Guideline on how to perform Doppler ultrasonography of the fetoplacental circulation. It is of the utmost importance not to expose the embryo or fetus to unduly harmful ultrasound energy, particularly in the earliest stages of pregnancy. At these stages, Doppler recording, when clinically indicated, should be performed at the lowest possible energy levels. ISUOG has published guidance on the use of Doppler ultrasound at the 11 to 13 + 6-week fetal ultrasound examination1. When performing Doppler imaging, the displayed thermal index should be ≤ 1.0 and the exposure time should be kept as short as possible, usually no longer than 5–10 min. It is not the intention of this Guideline to define clinical indications, specify appropriate timing of Doppler examination in pregnancy or discuss how to interpret findings or the use of Doppler in fetal echocardiography. The aim is to describe pulsed Doppler ultrasound and its different modalities: spectral Doppler, color flow mapping and power Doppler, which are commonly used to study the maternal–fetal circulation. We do not describe the continuous-wave Doppler technique, because this is not usually applied in obstetric imaging; however, in cases in which the fetus has a condition leading to very high-velocity blood flow (e.g. aortic stenosis or tricuspid regurgitation), it might be helpful in order to define clearly the maximum velocities by avoiding aliasing. The techniques and practices described in this Guideline have been selected to minimize measurement error and improve reproducibility. They may not be applicable in certain clinical conditions or for research protocols. Details of the grades of recommendation used in this Guideline are provided in Appendix 1. Reporting of levels of evidence is not applicable to this Guideline. All Doppler modalities are based on three fundamental principles. (1) Moving structures change the frequency and amplitude of reflected ultrasound signals. Moving structures include not only blood, but also fetal vessels or tissues. This can generate a shift in the backscattered signals. (2) Analysis of the components of the reflected signals are utilized for different Doppler modalities: the shift in frequency for directional color and spectral Doppler, and the shift in amplitude for power Doppler ultrasound (PDU). (3) All color and power Doppler modalities are pulsed techniques, while spectral Doppler can be pulsed or continuous. PRF, or scale, is the frequency at which the ultrasound signals (pulses) are emitted; a low PRF allows signals from slow-moving targets to reach the transducer before the next pulse is emitted, whereas a high PRF will allow only high velocities to reach the ultrasound transducer before the next pulse. The wall filter is a barrier defined by a specific threshold frequency below which signals are not displayed in the Doppler image. Gain is the amplification of signals. The quality and reproducibility of the recordings can be improved by knowledge of these Doppler settings and how to adjust them. Using real-time color Doppler ultrasound, the main branch of the uterine artery is located easily at the cervicocorporeal junction. Doppler velocimetry measurements are usually performed near to this location, either transabdominally2 or transvaginally3-5. While absolute velocities are of little or no clinical importance, semiquantitative assessment of the velocity waveforms is commonly employed. Measurements should be reported independently for the right and left uterine arteries, and the presence of notching should be noted. (GOOD PRACTICE POINT) Notching is defined qualitatively as reduced early diastolic velocities before the maximum diastolic velocity in the Doppler waveform. The severity of notching is defined by the difference between the lower early and the maximum diastolic velocities6. Note that, in women with congenital uterine anomaly, assessment of uterine artery Doppler indices and their interpretation is unreliable, since all published studies have been on women with (presumed) normal anatomy. (GOOD PRACTICE POINT) There is a significant difference in Doppler indices measured at the fetal end (intra-abdominal)11, in a free loop and at the placental end of the umbilical cord12. The impedance is highest at the fetal end, and absent/reversed EDV is likely to be seen first at this site. Reference ranges for umbilical artery Doppler indices at each of these sites have been published11, 13. For the sake of simplicity and consistency, by convention, measurements should be made in a free cord loop. (GOOD PRACTICE POINT) The decision to use a free loop of the cord was made early in the history of Doppler ultrasound and has been applied with great clinical success. However, in multiple pregnancies, and/or when comparing repeated measurements longitudinally, recordings from fixed sites, i.e. fetal end, placental end or intra-abdominal portion, may be more reliable. Appropriate reference ranges should be used according to the site of interrogation. Figure 3 shows examples of acceptable and unacceptable velocity waveform recordings and Figure 4 illustrates the influence of the vessel wall filter. Note that, in multiple pregnancy, assessment of umbilical artery blood flow can be challenging, since there may be difficulty in assigning a cord loop to a particular fetus. It is therefore better to sample the umbilical artery just distal to the abdominal insertion of the umbilical cord. However, the impedance there is higher than that in a free loop and that at the placental cord insertion, so appropriate reference charts are needed. (GOOD PRACTICE POINT) Note also that, in a two-vessel cord, at any gestational age, the diameter of the single umbilical artery is larger than the arterial diameter would be if there were two arteries14. Due to the different hemodynamics, the recorded velocity waveform in such cases should be interpreted with caution when using conventional reference ranges. (GOOD PRACTICE POINT) S/D ratio, RI and PI are the three best known indices to describe arterial flow velocity waveforms. All three are highly correlated. RI and S/D ratio estimate the relationship between PSV and EDV in the Doppler waveform (RI = (S − D)/S, S/D ratio = S/D, where S is peak systolic velocity and D is end-diastolic velocity). PI takes into account the PSV, the EDV and the time-averaged mean of the maximum frequency shift over the cardiac cycle (PI = (S − D)/TAMX, where S is peak systolic velocity, D is end-diastolic velocity and TAMX is the maximum velocity recorded in the MVE averaged over the cardiac cycle; TAMX should not be confused with time-averaged intensity-weighted mean velocity (TAV or Vm)). In Doppler waveforms showing dynamic changes in the systolic or diastolic components (i.e. in case of uterine artery waveform with presence of notching, or reversed EDV in umbilical artery waveform), PI gives a better estimate of the characteristics of the waveform than do RI or S/D ratio. PI shows a linear correlation with vascular resistance, as opposed to both S/D ratio and RI, which show a parabolic relationship with increasing vascular resistance31. Additionally, PI does not approach infinity when there are absent or reversed diastolic values. PI is the index recommended for use in clinical practice and research. (GOOD PRACTICE POINT) There is currently no high-level evidence to indicate how either CPR or UCR should be utilized in clinical management. Two indices are described for pulsed-wave Doppler analysis of the veins. The most commonly used is the pulsatility index for veins (PIV)32. This is calculated as PIV = (Vs − Va)/TAMX, where Vs is the peak forward velocity during ventricular systole and Va is the lowest forward velocity or peak reversed velocity during atrial contraction (the ‘a-wave’). The peak velocity index for veins (PVIV) is reported less frequently and is not featured on most auto-measure packages. PVIV is calculated as (Vs − Va)/Vd, where Vd is the peak forward velocity during atrial contraction (diastole). The use of PIV is recommended in clinical practice. (GOOD PRACTICE POINT) This Guideline presents the most commonly used techniques in clinical obstetrics, backed by solid scientific documentation. We are aware of important uses and sections of the circulation not mentioned herein, although these vessels and measurements may be of crucial importance in certain individuals. These vessels include, for example, the umbilical vein, hepatic artery, left portal vein and superior vena cava. However, the principles presented in this Guideline are valid for all fetal Doppler examinations. A. Bhide, Fetal Medicine Unit, St George's University Hospital and St George's University of London, London, UK G. Acharya, Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet & Center for Fetal Medicine, Karolinska University Hospital, Stockholm, Sweden and Women's Health and Perinatology Research Group, Faculty of Medicine, University of Tromsø and University Hospital of Northern Norway, Tromsø, Norway A. Baschat, Johns Hopkins Center for Fetal Therapy, Department of Gynecology & Obstetrics, Johns Hopkins University, Baltimore, MD, USA C. M. Bilardo, Department of Obstetrics and Gynecology Amsterdam UMC, Amsterdam and Academic Medical Center Groningen, University of Groningen, Groningen, The Netherlands C. Brezinka, Univ Klinik fuer Gynaekologie und Geburtshilfe, Innsbruck, Austria D. Cafici, Sociedad Argentina de Ultrasonografía en Medicina y Biología, Argentina C. Ebbing, Department of Obstetrics and Gynecology, Haukeland University Hospital, and Department of Clinical Medicine, University of Bergen, Bergen, Norway E. Hernandez-Andrade, Department of Obstetrics and Gynecology and Reproductive Sciences, McGovern Medical School, University of Texas, Health Science Center at Houston (UTHealth), Houston, TX, USA K. Kalache, Gynaecology, Charité, CBF, Berlin, Germany J. Kingdom, Maternal-Fetal Medicine Division, Department of Obstetrics & Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, Canada T. Kiserud, Department of Clinical Science, University of Bergen and Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway S. Kumar, Mater Research Institute, University of Queensland, Brisbane, Australia W. Lee, Texas Children's Fetal Center, Texas Children's Hospital Pavilion for Women, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA C. Lees, Centre for Fetal Care, Queen Charlotte's & Chelsea Hospital, Imperial College Healthcare NHS Trust, London, UK and Department of Development & Regeneration KU Leuven, Leuven, Belgium K. Y. Leung, Department of Obstetrics and Gynaecology, Queen Elizabeth Hospital, Hong Kong G. Malinger, Division of Ob-Gyn Ultrasound, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel G. Mari, Women's Health Institute, Department of Obstetrics and Gynecology, Cleveland Clinic Foundation, Cleveland, OH, USA F. Prefumo, Division of Obstetrics and Gynaecology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy W. Sepulveda, FETALMED – Maternal-Fetal Diagnostic Center, Fetal Imaging Unit, Santiago, Chile B. Trudinger, Department of Obstetrics and Gynaecology, University of Sydney, Sydney, Australia This Guideline should be cited as: ‘Bhide A, Acharya G, Baschat A, Bilardo CM, Brezinka C, Cafici D, Ebbing C, Hernandez-Andrade E, Kalache K, Kingdom J, Kiserud T, Kumar S, Lee W, Lees C, Leung KY, Malinger G, Mari G, Prefumo F, Sepulveda W, Trudinger B. ISUOG Practice Guidelines (updated): use of Doppler velocimetry in obstetrics. Ultrasound Obstet Gynecol 2021; 58: 331–339.’

PURPOSE: We elucidated the value of tumor-infiltrating lymphocytes (TIL) as an independent predictor for pathologic complete response (pCR) rate and as a prognostic marker for disease-free survival (DFS) in patients with HER2-positive breast cancer in the neoadjuvant setting. EXPERIMENTAL DESIGN: We evaluated stromal TILs in 498 HER2-positive breast cancer samples of the neoadjuvant GeparQuattro (G4) and GeparQuinto (G5) trials. Levels of TILs were determined as a continuous parameter per 10% increase and as lymphocyte-predominant breast cancer (LPBC; ≥ 60% TILs), and correlated with pCR rate and DFS. RESULTS: In the complete cohort, HER2-positive LPBC cases had a significantly increased pCR rates compared with non-LPBC types. They were significant predictors for pCR in univariate (10% TILs: OR 1.12, P = 0.002; LPBC: OR 2.02, P = 0.002) and multivariate analyses (10% TILs: OR 1.1, P = 0.014; LPBC: OR 1.87, P = 0.009). This effect was also detectable in the trastuzumab-treated (10% TILs: OR 1.12, P = 0.018; LPBC: OR 2.08, P = 0.013) but not in the lapatinib-treated subgroup. We identified a low-risk (pCR/LPBC) and a high-risk group (no pCR/no LPBC) regarding DFS. In triple-positive breast cancer, TILs are of more prognostic relevance than pCR. CONCLUSIONS: We could demonstrate the predictive and prognostic impact of TILs in HER2-positive breast cancer in the neoadjuvant setting. In combination with pCR rate, TILs may help to stratify prognostic subgroups, thereby guiding future therapy decisions. Clin Cancer Res; 22(23); 5747-54. ©2016 AACR.

BACKGROUND: The prognostic significance of isolated tumor cells (ITCs) in bone marrow (BM) from patients with breast carcinoma at the time of their primary diagnosis recently was been confirmed by a large pooled analysis. If the persistence of ITCs after adjuvant therapy confers a similar risk for recurrence, then it would be an indication to consider secondary adjuvant therapy. METHODS: The authors analyzed BM aspirates from 228 patients during recurrence-free follow-up at a median interval +/- standard deviation (SD) of 21.3 +/- 29.1 months after a primary diagnosis of breast carcinoma (pathologic T1 [pT1]-pT2, pN0-pN3, pM0). Carcinoma cells were detected using a standardized immunoassay with monoclonal antibody A45-B/B3 directed against cytokeratin (CK). Patients were followed for a median +/- SD of 49.8 +/- 32.1 months after their primary diagnosis. RESULTS: Persistent ITCs in BM were detected in 12.7% of patients (n=29 patients). Positive BM status was more frequent (15.7%) within the first 21 months after primary diagnosis than after a follow-up > 21 months (9.7%). The Kaplan-Meier estimate for mean recurrence-free survival was 149.7 months (95% confidence interval [95% CI], 139.6-159.8 months) in patients with negative BM status and 86.5 months (95% CI, 65.7-107.4 months; P=0.0003) in patients with positive BM status at the time patients underwent follow-up BM aspiration. Patients who were without evidence of persistent ITCs had a significantly longer overall survival (162.1 months; 95% CI, 152.1-172.0 months) compared with patients who had positive BM status (overall survival, 98.7 months; 95% CI, 79.7-117.9 months; P=0.0008). In multivariate Cox regression analysis that included BM status, tumor size, lymph node status, and histopathologic grade, evidence of ITCs was an independent significant predictor for reduced disease-free survival (relative risk [RR], 4.57; P <0.0001) and overall survival (RR, 5.57; P=0.002). Persistent ITCs had the greatest prognostic relevance when they were detected between 25 months and 42 months after primary diagnosis (RR, 7.68). CONCLUSIONS: Evidence of persistent ITCs in BM from patients with breast carcinoma indicated an increased risk for subsequent recurrence. Prospective trials should investigate the benefit of secondary adjuvant treatment on the basis of BM marrow status.

BACKGROUND AND METHODS: The clinical staging system of cervical cancer according to the International Federation of Gynecology and Obstetrics (FIGO) entails a large measure of subjectivity. This study analyzed the results of 1028 patients with cervical cancer at three reference centers. All patients had radical surgery, and all surgical specimens were processed as histologic giant sections with precise volumetry of the tumor. RESULTS: The interpretation of the histologic findings of parametrial invasion, vascular involvement, and lymph node involvement was found to differ somewhat among the three centers. However, all these findings were associated with tumor size. Survival rates correlated more consistently with tumor volume than with clinical or histologic stage. Five-year survival rates ranged from 91% for patients with tumors smaller than 2.5 cm3 to 70% for those with tumors 10-50 cm3. The 5-year survival rate of 24 patients with tumors larger than 50 cm3 (71% of whom had lymph nodes with positive findings) was 48%. Survival rates were identical among the three centers for patients with tumors smaller than 10 cm3, despite different degrees of surgical radicality. In contrast, more radical surgery was associated with significantly better survival rates in patients with larger tumors. CONCLUSIONS: The results of this study indicate that volumetry of the tumor permits a more accurate assessment of therapeutic results in patients with cervical cancer than does the FIGO classification. Pretherapeutic assessment of tumor volume is possible with magnetic resonance imaging. It seems that maximum parametrial resection is not necessary for patients with smaller tumors (smaller than 10 cm3), but truly radical surgery in patients with bulky tumors achieves better results than those usually expected in Stage IIb cervical cancer and at least comparable to those of radiation therapy.

Colposcopically directed cervical punch biopsies from 362 patients were screened by Southern blot hybridization for the presence of DNA of human papillomavirus (HPV) 6, 10, 11, 16, 18, 31 and 33. The biopsies represented original squamous epithelium, epithelium of metaplastic origin, different stages of cervical intraepithelial neoplasia (CIN) and invasive carcinomas. HPV6/11, 16, 18 and 31 were detected in 2.9% to 13.7% of histologically normal epithelia. HPV6/11 prevailed in CIN I. HPV16 was clearly more abundant than other HPV types in high-grade CIN and invasive cancers (50%-60%), compared with healthy epithelium. Restriction enzyme cleavage analysis of DNA from primary cancers and corresponding metastases proved the stable association of HPV16 DNA with invasive tumor cells. Preliminary follow-up studies of CIN II patients suggested that HPV16-associated lesions are relatively more likely to persist or to progress. Taken together, the data support the notion of a higher oncogenic potential of HPV16.

OBJECTIVE: To assess the contraceptive reliability, cycle control and tolerability of a new monophasic oral contraceptive containing 30 g ethinylestradiol plus 3 mg drospirenone (Yasmin, Schering AG, Berlin, Germany), it was compared with an established oral contraceptive containing 30 g ethinylestradiol plus 150 g desogestrel (Marvelon, NV Organon, Oss, The Netherlands). METHODS: A randomized, open-label, 13-cycle study was performed at 80 European centers. Contraceptive reliability, cycle control, blood pressure, body weight, the incidence of adverse events and skin condition were assessed during 13 cycles of oral contraceptive use, and at follow-up. Subjects recorded body weight on three consecutive days pretreatment and weekly thereafter. RESULTS: Of 2069 women who started the study and received the trial preparations in a ratio of 4:1 (ethinylestradiol/drospirenone, n = 1657; ethinylestradiol/desogestrel, n = 412), 1615 completed the 13 cycles plus follow-up, providing data for over 23,000 evaluable cycles. Eleven pregnancies occurred during treatment, only one of which (in the ethinylestradiol/drospirenone group) could not be ascribed to user failure or interaction with other factors. Both preparations provided effective contraception and cycle control. Pre-existing acne and seborrhea were improved and blood pressure was essentially unchanged. The two treatments differed in their effect on body weight, the difference being statistically significant. In the ethinylestradiol/drospirenone group, there was a distinct decrease over the whole treatment phase, while a subtle and less distinct decrease was documented in the ethinylestradiol/desogestrel group. CONCLUSIONS: The combination of 30 g ethinylestradiol/3 mg drospirenone provides effective oral contraception, excellent cycle control, good tolerability and a level of weight loss that may have a significant beneficial effect on compliance in women with a tendency to weight gain due to water retention.

Despite strong homology, the roles of TP53 and TP73 in tumorigenesis seem to be fundamentally different. In contrast to TP53, tumor-associated overexpression of TP73 in many different cancers, combined with virtual absence of inactivating mutations and lack of a cancer phenotype in the TP73 null mouse are inconsistent with a suppressor function but instead support an oncogenic function. The discovery of NH(2)-terminally truncated p73 isoforms, collectively called DeltaTAp73, is now the focus of intense interest because they act as potent transdominant inihibitors of wild-type p53 and transactivation-competent TAp73. Therefore, establishing deregulated DeltaTAp73 expression in tumors could be the crucial link to decipher which of the two opposing roles of this bipolar gene is the biologically relevant one. This study is the largest to date and encompasses 100 ovarian carcinomas with complete expression profile of all NH(2)-terminal isoforms, discriminating between TAp73 and DeltaTAp73 (DeltaNp73, DeltaN'p73, Ex2p73, and Ex2/3p73) by isoform-specific real-time reverse transcription-PCR. We find that the set of NH(2)-terminal p73 isoforms distinguishes ovarian cancer patients from healthy controls and thus is a molecular marker for this diagnosis. Ovarian cancers strongly and almost universally overexpress DeltaN'p73 compared with normal tissues (95% of cancers). About one-third of tumors also exhibit concomitant up-regulation of the antagonistic TAp73, whereas only a small subgroup of tumors overexpress DeltaNp73. Thus, deregulation of the E2F1-responsive P1 promoter, rather than the alternate P2 promoter, is mainly responsible for the production of transdominant p53/TAp73 antagonists in ovarian cancer. Tumor stage, grade, presence of metastases, p53 status, and residual disease after resection are significant prognostic markers for overall and recurrence-free survival. A trend is found for better overall survival in patients with low expression of DeltaN'p73/DeltaNp73, compared with patients with high expression. A strong correlation between deregulated DeltaTAp73 and p53 status exists. p53 wild-type cancers exhibit significantly higher deregulation of DeltaN'p73, DeltaNp73, and Ex2/3p73 than p53 mutant cancers. This data strongly supports the hypothesis that overexpression of transdominant p73 isoforms can function as epigenetic inhibitors of p53 in vivo, thereby alleviating selection pressure for p53 mutations in tumors.

Perinatal care of pregnant women at high risk for preterm delivery and of preterm infants born at the limit of viability (22-26 completed weeks of gestation) requires a multidisciplinary approach by an experienced perinatal team. Limited precision in the determination of both gestational age and foetal weight, as well as biological variability may significantly affect the course of action chosen in individual cases. The decisions that must be taken with the pregnant women and on behalf of the preterm infant in this context are complex and have far-reaching consequences. When counselling pregnant women and their partners, neonatologists and obstetricians should provide them with comprehensive information in a sensitive and supportive way to build a basis of trust. The decisions are developed in a continuing dialogue between all parties involved (physicians, midwives, nursing staff and parents) with the principal aim to find solutions that are in the infant's and pregnant woman's best interest. Knowledge of current gestational age-specific mortality and morbidity rates and how they are modified by prenatally known prognostic factors (estimated foetal weight, sex, exposure or nonexposure to antenatal corticosteroids, single or multiple births) as well as the application of accepted ethical principles form the basis for responsible decision-making. Communication between all parties involved plays a central role. The members of the interdisciplinary working group suggest that the care of preterm infants with a gestational age between 22 0/7 and 23 6/7 weeks should generally be limited to palliative care. Obstetric interventions for foetal indications such as Caesarean section delivery are usually not indicated. In selected cases, for example, after 23 weeks of pregnancy have been completed and several of the above mentioned prenatally known prognostic factors are favourable or well informed parents insist on the initiation of life-sustaining therapies, active obstetric interventions for foetal indications and provisional intensive care of the neonate may be reasonable. In preterm infants with a gestational age between 24 0/7 and 24 6/7 weeks, it can be difficult to determine whether the burden of obstetric interventions and neonatal intensive care is justified given the limited chances of success of such a therapy. In such cases, the individual constellation of prenatally known factors which impact on prognosis can be helpful in the decision making process with the parents. In preterm infants with a gestational age between 25 0/7 and 25 6/7 weeks, foetal surveillance, obstetric interventions for foetal indications and neonatal intensive care measures are generally indicated. However, if several prenatally known prognostic factors are unfavourable and the parents agree, primary non-intervention and neonatal palliative care can be considered. All pregnant women with threatening preterm delivery or premature rupture of membranes at the limit of viability must be transferred to a perinatal centre with a level III neonatal intensive care unit no later than 23 0/7 weeks of gestation, unless emergency delivery is indicated. An experienced neonatology team should be involved in all deliveries that take place after 23 0/7 weeks of gestation to help to decide together with the parents if the initiation of intensive care measures appears to be appropriate or if preference should be given to palliative care (i.e., primary non-intervention). In doubtful situations, it can be reasonable to initiate intensive care and to admit the preterm infant to a neonatal intensive care unit (i.e., provisional intensive care). The infant's clinical evolution and additional discussions with the parents will help to clarify whether the life-sustaining therapies should be continued or withdrawn. Life support is continued as long as there is reasonable hope for survival and the infant's burden of intensive care is acceptable. If, on the other hand, the health care team and the parents have to recognise that in the light of a very poor prognosis the burden of the currently used therapies has become disproportionate, intensive care measures are no longer justified and other aspects of care (e.g., relief of pain and suffering) are the new priorities (i.e., redirection of care). If a decision is made to withhold or withdraw life-sustaining therapies, the health care team should focus on comfort care for the dying infant and support for the parents.

Human papillomavirus (HPV) 16 is most prevalent in cervical cancers and also persists in metastases. We examined HPV16-DNA-positive primary cancers and several lymph nodes from each of 14 patients to evaluate the use of HPV16 DNA as a diagnostic marker for the detection of early node involvement. The HPV16 DNA was exclusively integrated in 39% of the primary cancers, predominantly episomal in 36%, and integrated and extrachromosomal to a similar extent in 25%. Thirteen of 16 involved lymph nodes contained HPV16 sequences. Integrated viral DNA showed the same pattern in primary tumors and in metastases. The level of extrachromosomal HPV16 DNA, however, appeared to be considerably reduced in some nodes. HPV16 DNA was also detected in 18 out of 59 histologically negative lymph nodes. This result recommends nucleic acid hybridization as a sensitive method for the detection of HPV-DNA-positive cancer cells. The prognostic significance of viral sequences in histologically negative nodes remains to be established.

Abstract Purpose The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer. Methods The process of updating the S3 guideline dating from 2012 was based on the adaptation of identified source guidelines which were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and the results of a systematic search of literature databases and the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point to develop recommendations and statements which were modified and graded in a structured consensus procedure. Recommendations Part 1 of this short version of the guideline presents recommendations for the screening, diagnosis and follow-up care of breast cancer. The importance of mammography for screening is confirmed in this updated version of the guideline and forms the basis for all screening. In addition to the conventional methods used to diagnose breast cancer, computed tomography (CT) is recommended for staging in women with a higher risk of recurrence. The follow-up concept includes suggested intervals between physical, ultrasound and mammography examinations, additional high-tech diagnostic procedures, and the determination of tumor markers for the evaluation of metastatic disease.

PURPOSE: This is an official interdisciplinary guideline, published and coordinated by the German Society of Gynaecology and Obstetrics (DGGG), the Austrian Society of Gynaecology and Obstetrics (OEGGG) and the Swiss Society of Gynaecology and Obstetrics (SGGG). The guideline was developed for use in German-speaking countries and is backed by the German Society of Anaesthesiology and Intensive Medicine (DGAI), the Society of Thrombosis and Haemostasis Research (GTH) and the German Association of Midwives. The aim is to provide a consensus-based overview of the diagnosis and management of peripartum bleeding obtained from an evaluation of the relevant literature. METHODS: This S2k guideline was developed from the structured consensus of representative members of the various professional associations and professions commissioned by the Guideline Commission of the DGGG. RECOMMENDATIONS: The guideline encompasses recommendations on definitions, risk stratification, prevention and management.

We report on a woman with Muellerian aplasia, renal and skeletal anomalies, and minor dysmorphic signs. Conventional cytogenetic analysis revealed mosaicism for a small supernumerary, undefinable ring chromosome. Chromosome microdissection and reverse painting demonstrated that this marker contained pericentric material from chromosome 8 (8p12q12). Thus, we identified a Muellerian aplasia phenotype with partial trisomy 8 mosaicism.

Abstract Purpose The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer. Method The process of updating the S3 guideline published in 2012 was based on the adaptation of identified source guidelines. They were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and with the results of a systematic search of literature databases followed by the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point and used them to develop suggestions for recommendations and statements, which were then modified and graded in a structured consensus process procedure. Recommendations Part 2 of this short version of the guideline presents recommendations for the therapy of primary, recurrent and metastatic breast cancer. Loco-regional therapies are de-escalated in the current guideline. In addition to reducing the safety margins for surgical procedures, the guideline also recommends reducing the radicality of axillary surgery. The choice and extent of systemic therapy depends on the respective tumor biology. New substances are becoming available, particularly to treat metastatic breast cancer.

As part of an ongoing analysis of limb deficiencies occurring among 1,213,913 consecutive livebirths in British Columbia during the years 1952-1984, all cases with deficiencies of the upper limbs were analysed with a view to identifying associated patterns of anomalies. This analysis resulted in seven subgroups. For each subgroup, incidence figures for cases with and without additional anomalies were calculated separately. The proportion of cases with additional anomalies varied markedly by subgroup. For example, 89% of cases with longitudinal defects of the radius had additional malformations, while only 28% of cases with transverse defects of the radius had other organ anomalies (chi 2 = 40.55; P < 0.001, one degree of freedom). A preponderance of males was found among the cases with associated defects, particularly in the group with longitudinal defects of the radius (28 males, 14 females; chi 2 = 14.10; P < 0.001). Clustering of specific patterns of associated malformations is described within subgroups.

Abstract Aims The aim of this official guideline published and coordinated by the German Society of Gynaecology and Obstetrics (DGGG) in cooperation with the Austrian Society for Gynaecology and Obstetrics (OEGGG) and the Swiss Society for Gynaecology and Obstetrics (SGGG) was to provide consensus-based recommendations for the diagnosis and treatment of endometriosis based on an evaluation of the relevant literature. Methods This S2k guideline represents the structured consensus of a representative panel of experts with different professional backgrounds commissioned by the Guideline Committee of the DGGG, OEGGG and SGGG. Recommendations Recommendations on the epidemiology, aetiology, classification, symptomatology, diagnosis and treatment of endometriosis are given and special situations are discussed.

Zusammenfassung Gestationsdiabetes (GDM) wird als Glukosetoleranzstörung definiert, die erstmals in der Schwangerschaft festgestellt wird. GDM ist mit einer erhöhten feto-maternalen Morbidität sowie Langzeitkomplikationen bei Mutter und Kind assoziiert. Frauen, die die Kriterien eines manifesten Diabetes mellitus bereits in der Frühschwangerschaft erfüllen (Nüchternplasmaglukose ≥ 126 mg/dl, Spontanglukosemessung ≥ 200 mg/dl oder HbA 1c ≥ 6,5 % vor der 20. Schwangerschaftswoche) sollen als Schwangere mit manifestem Diabetes klassifiziert und ebenso behandelt werden. Ein Screening auf unerkannten Typ 2 Diabetes bei der ersten pränatalen Kontrolle wird besonders bei Frauen mit hohem Risiko (Anamnese eines GDM/Prädiabetes, Fehlbildungen, Totgeburt, wiederholte Aborte oder Geburtsgewicht über 4500 g in früheren Schwangerschaften, Adipositas, metabolisches Syndrom, Alter &gt; 35 Jahre, bei Gefäßerkrankungen, Auftreten von Diabetessymptomen wie Glukosurie, ethnische Zugehörigkeit zu Gruppen mit hohem Risiko [arabisch, S und SO-asiatisch, lateinamerikanisch]) empfohlen. GDM wird durch einen oralen Glukosetoleranztest (oGTT, 120 min; 75 g Glukose) oder durch Nüchternplasmaglukose ≥ 92 mg/dl diagnostiziert. Bei hohem Risiko kann ein oGTT bereits im ersten Trimenon sinnvoll sein, zwischen der 24.–28. Schwangerschaftswoche muss dieser Test aber in jedem Fall bei allen Schwangeren mit bis dahin unauffälligen Glukosewerten im Rahmen der Mutter-Kind-Pass-Untersuchung durchgeführt werden. Nach WHO Empfehlungen basierend auf der „Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study“ liegt ein GDM vor, wenn die Plasmaglukose nüchtern 92 mg/dl, nach 60 min 180 mg/dl oder nach 120 min 153 mg/dl überschreitet (Internationale Konsensuskriterien). Ein einziger erhöhter Wert ist für die Diagnose ausreichend und bedarf bereits einer strikten Stoffwechselkontrolle. Nach bariatrischer Operation wird aufgrund der Gefahr einer postprandialen Hypoglykämie die Durchführung eines oGTT nicht empfohlen. Alle Frauen mit GDM müssen eine Ernährungsberatung erhalten und ihre Blutzuckerwerte (4 Messzeitpunkte) regelmäßig kontrollieren. Ebenso sollte, falls nicht kontraindiziert, die körperliche Aktivität erhöht werden. Falls die Blutzuckerspiegel nicht im Therapiezielbereich liegen (nüchtern &lt; 95 mg/dl und 1 h postprandial &lt; 140 mg/dl, Evidenzklasse B) soll als erste Wahl eine Insulintherapie initiiert werden (Evidenzklasse A). Neben der mütterlichen Stoffwechselüberwachung sind geburtshilfliche Kontrollen und ein ultraschallgestütztes, fetales Monitoring notwendig, um die mütterliche und fetale/neonatale Morbidität und die perinatale Mortalität möglichst gering zu halten (Evidenzklasse A). Im Rahmen der neonatalen Untersuchungen müssen bei Neugeborenen von Müttern mit GDM Blutzuckerkontrollen erfolgen und bei Erfordernis geeignete Maßnahmen eingeleitet werden. Nach der Entbindung (4–12 Wochen post partum) wird neuerlich die Durchführung eines oGTT (75 g; WHO Kriterien) bei allen Frauen mit GDM empfohlen, um eine über die Schwangerschaft hinaus bestehende Glukosetoleranzstörung auszuschließen. Bei Normalbefund sollen alle 2–3 Jahre regelmäßig weitere Testungen (Nüchternblutzucker, Spontanglukose, HbA 1c oder oGTT) erfolgen (Evidenzklasse B). Alle Frauen sollen über ihr deutlich erhöhtes Risiko für Typ 2 Diabetes, das höhere kardiovaskuläre Risiko, sowie über entsprechende Präventionsmaßnahmen, informiert werden. Dazu gehören Lebensstilmaßnahmen, wie Gewichtsreduktion bei Übergewicht, gesunde Ernährung und ausreichend körperliche Aktivität (Evidenzklasse A). Auch die Kinder sollen hinsichtlich einer unauffälligen Entwicklung regelmäßig nachuntersucht werden, da in rezenten Untersuchungen höheres Risiko für Übergewicht und Adipositas sowie erhöhte Glukoseparameter festgestellt wurden. Wenn möglich sollte die gesamte Familie über Lebensstilmaßnahmen zur Aufrechterhaltung/Verbesserung der Gesundheit informiert werden.

PURPOSE The PAOLA-1/ENGOT-ov25 trial of maintenance olaparib plus bevacizumab for newly diagnosed advanced high-grade ovarian cancer demonstrated a significant progression-free survival (PFS) benefit over placebo plus bevacizumab, particularly in patients with homologous recombination deficiency (HRD)–positive tumors. We explored whether mutations in non- BRCA1 or BRCA2 homologous recombination repair (non–BRCA HRRm) genes predicted benefit from olaparib plus bevacizumab in PAOLA-1. METHODS Eight hundred and six patients were randomly assigned (2:1). Tumors were analyzed using the Myriad MyChoice HRD Plus assay to assess non–BRCA HRRm and HRD status; HRD was based on a genomic instability score (GIS) of ≥ 42. In this exploratory analysis, PFS was assessed in patients harboring deleterious mutations using six non–BRCA HRR gene panels, three devised for this analysis and three previously published. RESULTS The non–BRCA HRRm prevalence ranged from 30 of 806 (3.7%) to 79 of 806 (9.8%) depending on the gene panel used, whereas 152 of 806 (18.9%) had non‐ BRCA1 or BRCA2 mutation HRD-positive tumors. The majority of tumors harboring non–BRCA HRRm had a low median GIS; however, a GIS of &gt; 42 was observed for tumors with mutations in five HRR genes ( BLM, BRIP1, RAD51C, PALB2, and RAD51D). Rates of gene-specific biallelic loss were variable (0% to 100%) in non–BRCA HRRm tumors relative to BRCA1-mutated (99%) or BRCA2-mutated (86%) tumors. Across all gene panels tested, hazard ratios for PFS (95% CI) ranged from 0.92 (0.51 to 1.73) to 1.83 (0.76 to 5.43). CONCLUSION Acknowledging limitations of small subgroup sizes, non–BRCA HRRm gene panels were not predictive of PFS benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in PAOLA-1, irrespective of the gene panel tested. Current gene panels exploring HRRm should not be considered a substitute for HRD determined by BRCA mutation status and genomic instability testing in first-line high-grade ovarian cancer.

Aims: The aim was to establish an official interdisciplinary guideline, published and coordinated by the German Society of Gynecology and Obstetrics (DGGG). The guideline was developed for use in German-speaking countries. In addition to the Germany Society of Gynecology and Obstetrics, the guideline has also been approved by the Swiss Society of Gynecology and Obstetrics (SGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). This is a guideline published and coordinated by the DGGG. The aim is to provide evidence-based recommendations obtained by evaluating the relevant literature for the diagnostic, conservative and surgical treatment of women with female pelvic organ prolapse with or without stress incontinence. Methods: We conducted a systematic review together with a synthesis of data and meta-analyses, where feasible. MEDLINE, Embase, Cinahl, Pedro and the Cochrane Register were searched for relevant articles. Reference lists were handsearched, as were the abstracts of the Annual Meetings of the International Continence Society and the International Urogynecological Association. We included only abstracts of randomized controlled trials that were presented and discussed in podium sessions. We assessed original data on surgical procedures published since 2008 with a minimum follow-up time of at least 12 months. If the studies included descriptions of perioperative complications, this minimum follow-up period did not apply. Recommendations: The guideline encompasses recommendations for the diagnosis and treatment of female pelvic organ prolapse. Recommendations for anterior, posterior and apical pelvic organ prolapse with or without concomitant stress urinary incontinence, uterine preservation options, and the pros and cons of mesh placements during surgery for pelvic organ pro-Zusammenfassung !