Real world data analysis of next generation sequencing and protein expression in metastatic breast cancer patients.

Next generation sequencing (NGS) together with protein expression analysis is back bone of molecularly targeted therapy in precision medicine. Our retrospective study shows our experience with NGS of 324 genes in combination with protein expression in patients with advanced breast cancer (aBC). The primary purpose was to analyze the prevalence of individual genetic alterations combined with protein expression to define potential targets for an individualized therapy. Between April 2018 and September 2019, 41 patients with aBC were offered a NGS test. The test was used to detect clinically relevant genomic alterations and to support further targeted therapy decisions. Hormone receptors, ERBB2 of tumors and PD-L1 was stained by immunohistochemistry. The data was recorded up to September 2019. After prior consent 41 results were available for further analysis. The most common BC subtypes were triple-negative (n = 16), HR+/ERBB2- (n = 15), and ERBB2+ (n = 9), with one missing data of the primary tumor. 27 patients had more than one genetic alteration. The most common alterations were PIK3CA (n = 14) and ERBB2 alterations (n = 11). Followed by ESR1 (n = 10), FGFR1 (n = 7) and PTEN (n = 7). 68% of the alterations were clinically relevant (tier I and II of ESCAT classification). The most common treatment recommendation was ERBB2-directed therapy (single or double blockade, trastuzumab emtansine and lapatinib) followed by alpelisib in combination with fulvestrant. Comprehensive genomic profiling combined with protein expression analysis in aBC allowed a guided personalized therapy for half of our patients. So far there are no well-defined tools allowing interpretations of genomic alterations detected by NGS in combination with protein expression and other factors.

Effect of early "quilting" sutures on morbidity in postpartum hemorrhage.

OBJECTIVE: To examine whether "quilting" sutures are safe and effective in preventing hysterectomy among women with postpartum hemorrhage (PPH) and whether early application might reduce the incidence of transfusion. METHODS: Data were reviewed from women treated via quilting sutures after cesarean delivery at a university hospital between 2007 and 2016. Objective and subjective data were collected by analyzing medical records and performing telephone interviews. To observe trends during the study period, data from the first 50% of women treated were compared with those from the second 50%. RESULTS: Overall, 26 cesareans with quilting sutures were performed. Two hysterectomies could not be avoided. During 2012-2106, 18 quilting sutures were performed as compared with 8 in 2007-2011, pointing to a more liberal indication. Intensive care was required twice as frequently among the first 13 procedures than among the second 13 procedures (10 vs 5, respectively). A similar observation was made for the use of blood transfusions or clotting activation (9 vs 4, respectively). Three women who desired to have a child subsequently delivered a newborn. CONCLUSION: Quilting sutures were found to be a safe and simple technique to prevent hysterectomies in PPH. Morbidity was reduced when the decision to perform sutures was taken early.

Emergent surgical pulmonary embolectomy in a pregnant woman: case report and literature review.

Acute pulmonary embolism is a leading cause of death during pregnancy and delivery in the United States. We describe the case of a 25-year-old woman who presented in cardiogenic shock in week 38 of her first pregnancy. After the emergent cesarean delivery of a healthy male neonate, the mother underwent immediate surgical pulmonary embolectomy. We confirmed the diagnosis of pulmonary embolism intraoperatively by means of transesophageal echocardiography and removed large clots from the patient's pulmonary arteries. Mother and child were doing well, 27 months later. In addition to presenting our patient's case, we discuss the other relevant reports and the options for treating massive pulmonary embolism during pregnancy.

Cell-free fetal DNA and adverse outcome in low risk pregnancies.

OBJECTIVE: To analyze in a large prospective cohort study of low risk pregnancies whether cell-free fetal (cff) DNA in maternal plasma of the second trimester might be associated with the development of preeclampsia, preterm delivery, and small for gestational age. STUDY DESIGN: A subset of a large prospective cohort study in serological RhD negative pregnant women with RHD positive fetuses was used. Cff DNA was determined through the detection of RHD specific sequences with real-time PCR. RESULTS: In 611 pregnancies, rates of 7.2% preeclampsia, 1.6% preterm birth ≤32, 2.9% ≤34, and 12.4% ≤37 weeks of gestation, 5.7% of small for gestational age <5th percentile, and 8.2% <10th percentile were observed. For none of these risk groups an association with cff DNA could be established. CONCLUSION: Cff DNA in maternal plasma of the second trimester was not found to be a marker for an adverse pregnancy outcome in low risk pregnancies.

The impact of the time interval between two successive deliveries in an obstetric unit in terms of the mode of each delivery and the rate of perinatal mortality.

OBJECTIVE: To analyze the relationship of the time interval between two deliveries, done by one obstetric team, on the delivery mode of the subsequent birth; to define the length of this interval; and to evaluate this time interval as a risk factor for increased perinatal mortality in a population-based cohort. METHODS: All singleton deliveries at ≥ 24 weeks' gestation in Lower Saxony, Germany, between 2001 and 2005 (a total of 317,663 deliveries including 402 cases of perinatal mortality) were analyzed. The mode of the previous and the subsequent delivery, the time interval between the two deliveries, the time of birth, the hospital volume, and the existence of an affiliated neonatal ward were investigated. RESULTS: When the first vaginal delivery was <45 min, there was a reduced probability that the subsequent birth would be a cesarean section. In case of a previous cesarean section, the cesarean rate of the following birth was influenced up to 165 min. In a multivariate analysis, vaginal deliveries following an earlier vaginal birth and occurring within <45 min were associated with increased perinatal mortality. Repeated cesarean sections within <165 min were associated with increased perinatal mortality when occurring at night or on weekends. CONCLUSION: A short time interval between two deliveries in an obstetric unit constitutes an independent risk factor for perinatal mortality.

Cell-free fetal DNA in specimen from pregnant women is stable up to 5 days.

OBJECTIVE: Before noninvasive prenatal diagnosis on the fetal Rhesus D status (NIPD RhD) can be implemented on a mass-scale, it is crucial to define requirements regarding sample transport. The aim of this study was to determine the relation between the transport time of samples for NIPD and the concentration of fetal DNA in maternal plasma. METHOD: We analyzed qualitative and quantitative data obtained in a previous study performed with real-time PCR to determine the accuracy of NIPD RhD following two different DNA extraction protocols. The number of days from phlebotomy until freezing of plasma at the study site was recorded and defined as transport time. RESULTS: NIPD RhD results of 972 specimens were analyzed according to transport time, which varied from a few hours to a maximum of 8 days (median 2 days). No decrease of cell-free fetal DNA was observed in samples with less than 6 days transport time. There was a pivotal trend to higher cycle threshold values in samples with ≥ 6 days transport time compared with those with ≤ 5 days. CONCLUSION: Because only a few laboratories offer an NIPD RhD service, we suggest a maximal transport time of 5 days from phlebotomy until freezing at the testing laboratory.

Peripartum cardiomyopathy--a new treatment option by inhibition of prolactin secretion.

Peripartum cardiomyopathy (PPCM) is a rare disease of unclear etiology with a frequent poor outcome, despite optimal medical therapy. Recent experimental data implicate a causal role of prolactin. We report a patient with PPCM who responded well to treatment with Bromocriptine in addition to standard therapy of heart failure.

The determination of the fetal D status from maternal plasma for decision making on Rh prophylaxis is feasible.

BACKGROUND: Noninvasive fetal RHD genotyping might become a valuable tool in decision making on antenatal Rh prophylaxis, which is currently in routine practice for all D- pregnancies in several countries. This study provides a large-scale validation study of this technology to address questions concerning feasibility and applicability of its introduction into clinical routine. STUDY DESIGN AND METHODS: Real-time polymerase chain reaction (PCR) targeting RHD Exons 5 and 7 was applied for the detection of fetal-specific RHD sequences in maternal plasma. A total of 1113 women in 6 to 32 weeks (median, Week 25) of pregnancy were recruited. All of them were serologically typed as D- according to current German guidelines. DNA was extracted via a spin-column method and a novel automated approach using magnetic tips. Real-time PCR results were compared with postnatal serology and discrepancies further elucidated by DNA sequencing from a newborn's buccal swab. RESULTS: Sensitivities of fetal RHD genotyping were 99.7 percent (spin columns) and 99.8 percent (magnetic tips), thus comparable with serology (99.5%). The detection of weak D variants was more reliable by real-time PCR. Specificities of fetal RHD genotyping were 99.2 percent (spin columns) and 98.1 percent (magnetic tips), which is lower than serology (>99.7%). Automation achieved significantly higher yields of cell-free fetal DNA. CONCLUSION: This prospective clinical trial revealed that routine determination of the fetal D status from maternal plasma is feasible. Noninvasive fetal RHD genotyping can be considered as sensitive as the traditional postnatal serologic assay.

Twin-to-twin delivery time interval: influencing factors and effect on short-term outcome of the second twin.

BACKGROUND: Following vaginal delivery of the first twin, the further management to deliver the second twin is in dispute. Controversial discussions have taken place on the importance of the time interval between the birth of the first and the second twin. OBJECTIVE: To evaluate factors influencing twin-to-twin delivery time interval, and short-term outcome of the second twin in a complete population-based cohort in Hesse, Germany. Study design. In a population-based cohort study, between January 1990 and December 2004, all twin pregnancies of > or =34+0 weeks' gestation with a vaginally delivered first twin were evaluated. Pregnancies with intrauterine death of either one of the twins before the onset of labour, complicated by twin-twin transfusion or fetal malformations were excluded. Some 4,110 twin pregnancies were analysed. Maternal and fetal characteristics for an increased twin-to-twin delivery time interval and its impact on an adverse short-term neonatal outcome, and the effect of the twin-to-twin delivery interval on umbilical arterial pH and base excess of the second twin have been investigated. RESULTS: In univariate analysis, breech, transverse lie, birth weight discordance with the second twin > or =20% larger, fetal distress, vaginal operative delivery, and caesarean section were associated with an increased time interval. Maternal characteristics were not related to an increased time interval. Increasing time interval was related to a decline in the mean umbilical arterial pH and base excess, and fetal acidosis, Apgar score <7 after 1, 5 and 10 min. In multivariate analysis, birth weight discordance, mode of delivery, and twin-to-twin delivery time interval were associated with an adverse short-term outcome of the second twin. CONCLUSION: As twin-to-twin delivery time interval seems to be an independent risk factor for adverse short-term outcome of the second twin, it should be kept short.

Twenty-four-hour CTG monitoring: comparison of normal pregnancies of 25-30 weeks of gestation versus 36-42 weeks of gestation.

OBJECTIVE: Routinely antepartal cardiotocogram (CTG) is recorded for 30 min in order to obtain normal resting phases (<30 min) or a decrease of irregulatory due to hypoxia (>30 min) or to differentiate these from each other. In case of early onset of hypoxia first pathological findings might only be seen by chance in incidentally recorded CTG. The goal of this study was, if a continuous 24-h CTG allows an earlier detection of beginning hypoxia in case of normal pregnancies of 36-42 weeks compared to pregnancies of 25-30 weeks of gestation, and if there are any differences between both groups concerning the qualitative and quantitative description or the detection of a circadian rhythm. METHODS: 21 patients in each group had 24-h CTGs by means of telemetry (Hewlett-Packard type 78101A, 80110A). In both study groups, fetal heart-rate tracing included a full qualitative and quantitative description. Comparison of the results of both groups was done to look for early signs of pathological findings concerning reduced fetal well-being and a potential day and night rhythm. RESULTS: In comparison to 36-42 weeks of pregnancies 25-30 weeks had significantly more physiological undulatory oscillation and less narrowed undulatory oscillation (P < 0.001), as well as less resting phases (P < 0.001). Baseline tachycardia and bradycardia showed significantly increasing quantity (P < 0.001). CONCLUSION: Twenty-four-hour CTG is a good screening method to detect early onset of hypoxia in case of second and third trimester pregnancies and a big help to detect a fetus at risk earlier. In future computerized CTG-systems should be proved in this connection and should be compared with our study.

Impact of fetal blood sampling on vaginal delivery and neonatal outcome in deliveries complicated by pathologic fetal heart rate: a population based cohort study.

OBJECTIVE: To compare the impact of electronic fetal monitoring (EFM) alone vs. EFM with additional fetal blood sampling (FBS) in vaginal deliveries complicated by pathologic fetal heart rate (FHR). METHODS: All deliveries in Hesse between 1990 and 2000 were evaluated for participation in this study. Inclusion criteria comprised (1) pathologic fetal heart rate, (2) singleton pregnancy, (3) cephalic presentation, (4) vaginal delivery, and (5) gestational age at delivery of more than 35 weeks' gestation. In order to analyze the meaning of additional risk factors at birth for the effectiveness of FBS two subgroups were selected depending on the presence of additional risk factors at birth. To examine the impact of FBS in deliveries with pathologic FHR on the mode of delivery and on neonatal outcome, univariate regression analysis was performed and odds ratios (OR) and their corresponding 95% confidence intervals (95% CI) were calculated. RESULTS: The study population comprised 49,560 deliveries, among deliveries complicated by pathologic FHR, 26% underwent FBS. Deliveries with pathologic FHR and controlled by FBS, with no additional antepartum risk factors, were associated with an increase in spontaneous births OR 1.41 (95% CI 1.27-1.58), and in the presence of additional risk factors OR 1.24 (1.19-1.30). Short-term neonatal outcome parameters were characterized by a lower frequency of severe fetal acidosis (umbilical artery pH <7.0) OR 0.55 (0.42-0.72), and Apgar score <5 after 5 min, OR 0.71 (0.55-0.90). CONCLUSION: In vaginal deliveries with pathologic FHR the use of FBS as an additional means of intrapartum fetal surveillance is associated with less vaginal operative deliveries, and with an improved short-term neonatal outcome.

Assessment of fetal lung development by quantitative ultrasonic tissue characterization: a methodical study.

OBJECTIVES: This study was performed to evaluate the quantitative ultrasonic tissue characterization of the normal fetal lung development by using acoustic raw data captured after preprocessing. METHODS: One hundred and sixty-two patients with completed gestational ages between 22 and 37 weeks were enrolled in this study. Longitudinal and transverse sections of the fetal thorax and upper abdomen were imaged. A region of interest of constant size was defined and the tissue-specific gray scale was determined by using an interactive software. RESULTS: A total of 162 patients met the inclusion criteria. The echogenicity of the fetal lung showed a particular changing pattern during pregnancy: the mean gray value of the fetal lung (MGV) is almost the same as the MGV of the fetal liver at 22 and 23 weeks, decreases between 22 and 31 weeks and increases between 31 and 37 weeks. The MGV of the fetal liver decreases significantly from 24 weeks to 31 weeks and increases significantly again toward 37 weeks. We stated that the MGV of the lung is smaller than the MGV of the liver during 31 weeks of gestation and the relation reverses in late gestation. At term, the MGV of the liver is greater than the MGV of the lung. The lung-to-liver ratio is <1 between 24 and 29 weeks and >1 between 30 and 35 weeks. CONCLUSION: The echogenicity of the fetal lung showed a particular changing pattern during pregnancy, which corresponds to morphologic changes of the fetal lung development.