Minimally Invasive Breast Biopsy After Neoadjuvant Systemic Treatment to Identify Breast Cancer Patients with Residual Disease for Extended Neoadjuvant Treatment: A New Concept.

BACKGROUND: Breast cancer patients with residual disease after neoadjuvant systemic treatment (NAST) have a worse prognosis compared with those achieving a pathologic complete response (pCR). Earlier identification of these patients might allow timely, extended neoadjuvant treatment strategies. We explored the feasibility of a vacuum-assisted biopsy (VAB) after NAST to identify patients with residual disease (ypT+ or ypN+) prior to surgery. METHODS: We used data from a multicenter trial, collected at 21 study sites (NCT02948764). The trial included women with cT1-3, cN0/+ breast cancer undergoing routine post-neoadjuvant imaging (ultrasound, MRI, mammography) and VAB prior to surgery. We compared the findings of VAB and routine imaging with the histopathologic evaluation of the surgical specimen. RESULTS: Of 398 patients, 34 patients with missing ypN status and 127 patients with luminal tumors were excluded. Among the remaining 237 patients, tumor cells in the VAB indicated a surgical non-pCR in all patients (73/73, positive predictive value [PPV] 100%), whereas PPV of routine imaging after NAST was 56.0% (75/134). Sensitivity of the VAB was 72.3% (73/101), and 74.3% for sensitivity of imaging (75/101). CONCLUSION: Residual cancer found in a VAB specimen after NAST always corresponds to non-pCR. Residual cancer assumed on routine imaging after NAST corresponds to actual residual cancer in about half of patients. Response assessment by VAB is not safe for the exclusion of residual cancer. Response assessment by biopsies after NAST may allow studying the new concept of extended neoadjuvant treatment for patients with residual disease in future trials.

How automated techniques ease functional assessment of the fetal heart: Applicability of two-dimensional speckle-tracking echocardiography for comprehensive analysis of global and segmental cardiac deformation using fetalHQ®.

BACKGROUND: Prenatal echocardiographic assessment of fetal cardiac function has become increasingly important. Fetal two-dimensional speckle-tracking echocardiography (2D-STE) allows the determination of global and segmental functional cardiac parameters. Prenatal diagnostics is relying increasingly on artificial intelligence, whose algorithms transform the way clinicians use ultrasound in their daily workflow. The purpose of this study was to demonstrate the feasibility of whether less experienced operators can handle and might benefit from an automated tool of 2D-STE in the clinical routine. METHODS: A total of 136 unselected, normal, singleton, second- and third-trimester fetuses with normofrequent heart rates were examined by targeted ultrasound. 2D-STE was performed separately by beginner and expert semiautomatically using a GE Voluson E10 (FetalHQ®, GE Healthcare, Chicago, IL). Several fetal cardiac parameters were calculated (end-diastolic diameter [ED], sphericity index [SI], global longitudinal strain [EndoGLS], fractional shortening [FS]) and assigned to gestational age (GA). Bland-Altman plots were used to test agreement between both operators. RESULTS: The mean maternal age was 33 years, and the mean maternal body mass index prior to pregnancy was 24.78 kg/m2. The GA ranged from 16.4 to 32.0 weeks (average 22.9 weeks). Averaged endoGLS value of the beginner was -18.57% ± 6.59 percentage points (pp) for the right and -19.58% ± 5.63 pp for the left ventricle, that of the expert -14.33% ± 4.88 pp and -16.37% ± 5.42 pp. With increasing GA, right ventricular endoGLS decreased slightly while the left ventricular was almost constant. The statistical analysis for endoGLS showed a Bland-Altman-Bias of -4.24 pp ± 8.06 pp for the right and -3.21 pp ± 7.11 pp for the left ventricle. The Bland-Altman-Bias of the ED in both ventricles in all analyzed segments ranged from -.49 mm ± 1.54 mm to -.10 mm ± 1.28 mm, that for FS from -.33 pp ± 11.82 pp to 3.91 pp ± 15.56 pp and that for SI from -.38 ± .68 to -.15 ± .45. CONCLUSIONS: Between both operators, our data indicated that 2D-STE analysis showed excellent agreement for cardiac morphometry parameters (ED and SI), and good agreement for cardiac function parameters (EndoGLS and FS). Due to its complexity, the application of fetal 2D-STE remains the domain of scientific-academic perinatal ultrasound and should be placed preferably in the hands of skilled operators. At present, from our perspective, an implementation into clinical practice "on-the-fly" cannot be recommended.

Latissimus dorsi flap for breast reconstruction: a large single-institution evaluation of surgical outcome and complications.

PURPOSE: The use of autologous tissues is considered gold standard for patients undergoing breast reconstruction and is the preferred method in the post-radiation setting. Although the latissimus dorsi flap (LDF) has been replaced by abdominal flaps as technique of choice, it remains a valuable option in several specific clinical situations and its use has been regaining popularity in recent years. In this work, we present an 18-year retrospective analysis of a single-institution single-surgeon experience with LDF-based reconstruction with focus on early complications and reconstructive failures. METHODS: Hospital records of all patients undergoing breast surgery for any reason in the Certified Breast Cancer Center, Regio Klinikum Pinneberg, Germany between April, 1st 2005 and October, 31st 2022 were reviewed. 142 consecutive LDF-based reconstructive procedures were identified. Detailed information was gathered on patient characteristics, treatment-related factors, and complications. RESULTS: One hundred forty patients (139 female, 1 male) received 142 LDF-based surgeries. The flap was used mainly for immediate breast reconstruction with or without implant (83% of patients), followed by defect coverage after removal of a large tumor (7%), implant-to-flap conversion with or without placement of a new implant (6%), and delayed post-mastectomy reconstruction (4%). The use of LDF decreased between 2005 and 2020 (2005: 17, 2006: 13, 2007: 14, 2008: 16, 2009: 5, 2010: 9, 2011: 8, 2012: 3, 2013: 10, 2014: 8, 2015: 8, 2016: 7, 2017: 7, 2018: 4, 2019: 4, 2020: 2, 2021: 6, 2022: 4). Surgery was performed for invasive breast cancer in 78%, ductal carcinoma in situ in 20% and other reasons such as genetic mutation in 1% of patients. Ipsilateral radiation therapy was received by 12% of patients prior to LDF surgery and by 37% after the surgery. 25% of patients were smokers. The median duration of surgery, including all procedures conducted simultaneously such as e.g., mastectomy, axillary surgery, or implant placement, was 117 min (range 56-205). Patients stayed in the hospital for a median of 7 days (range 2-23 days). The most common complication was seroma (26%), followed by wound dehiscence (8%), surgical site infection (7%), partial skin and/or nipple necrosis of any size (7%) and hematoma requiring surgical evacuation (2%). 19% of all patients required seroma aspiration or drainage, mostly at the donor site and performed under ultrasound guidance in the ambulatory setting. Flap loss due to necrosis occurred in 2% of patients. CONCLUSIONS: Latissimus dorsi flap is a well-established surgical technique commonly used for immediate breast reconstruction as well as defect coverage in locally advanced breast cancer. To the best of our knowledge, this is one of the largest single-surgeon analyses of early complications in patients receiving LDF. As expected, seroma was the most common complication observed in nearly one third of patients and requiring a therapeutic intervention in every fifth patient. Serious adverse events occurred rarely, and flap loss rate was very low.

Use and Impact of Pessary, Cerclage, and Progesterone for the Secondary Prevention of Preterm Birth: Data from the German Neonatal Network.

BACKGROUND: To evaluate the use and effect of cervical stitch cerclage, pessary, and progesterone on pregnancy outcome in mothers of very low birth weight infants (VLBWI) born<32 weeks of gestation in the German Neonatal Network (GNN). METHODS: The GNN is a population-based cohort study enrolling VLBWI since 2009. We included 575 neonates from 424 mothers into our analysis, who were born between 2015 and 2019, after prenatal intervention with cerclage, pessary, progesterone or a combination between 20/0 to 25/0 weeks of gestation to prevent preterm birth. Median intervention-to-birth interval was the primary endpoint. RESULTS: 231 of 424 pregnant women had a cerclage only (54.5%), 76 women a pessary only (17.9%), and 27 were prescribed progesterone only (15.3%). The most common combination treatment (>1 intervention group) was cerclage plus progesterone (n=27), followed by cerclage plus pessary (n=13). The median intervention-to-birth interval for the whole cohort was 24 days (IQR 19.0 days). The earlier the intervention was started, the longer the intervention-to-birth interval lasted: When started at 20 weeks, the interval was 34 days in contrast to 11.5 days, when started at 25 weeks. The >1 group was born at a significantly higher median GA with 27.0 weeks (IQR 2.9 weeks) and a higher median birth weight of 980 g (IQR 394 g) accordingly. CONCLUSION: We propose that the earliest possible start of intervention leads to the most efficient pregnancy prolongation.

Timing of antenatal steroid administration for imminent preterm birth: results of a prospective observational study in Germany.

PURPOSE: To evaluate the timing of antenatal steroid administration and associated medical interventions in women with imminent preterm birth. METHODS: We performed a prospective observational study at a single tertiary center in Germany from September 2018 to August 2019. We included pregnant women who received antenatal steroids for imminent preterm birth and evaluated the interval from administration to birth. 120 women with antenatal steroid application were included into our analysis. Descriptive statistics were performed to analyze factors influencing the timing of antenatal steroids and to evaluate additional medical interventions which women with imminent preterm birth experience. RESULTS: Of the 120 women included into our study, 35.8% gave birth before 34/0 weeks and 64.2% before 37/0 weeks of gestation. Only 25/120 women (20.8%) delivered within the optimal time window of 1-7 days after antenatal steroid application. 5/120 women (4.2%) only received one dose of antenatal steroids before birth and 3/120 (2.5%) gave birth within 8 to 14 days after antenatal steroids. Most women gave birth more than 14 days after steroid application (72.5%, 87/120). Women with preeclampsia (60%), PPROM (31%), and FGR (30%) had the highest rates of delivery within the optimal time window. Women of all timing groups received additional interventions and medications like antibiotics, tocolytics, or anticoagulation. CONCLUSION: Our observational data indicate that most pregnant women do not give birth within 7 days after the administration of antenatal steroids. The timing was best for preterm birth due to preeclampsia, PPROM, and FGR. Especially for women with symptoms of preterm labor and bleeding placenta previa, antenatal steroids should be indicated more restrictively to improve neonatal outcome and reduce untimely and unnecessary interventions.

Primary ovarian leiomyoma: a rare ovarian tumour.

After performing laparoscopic unilateral adnexectomy in a 53-year-old woman for a rapidly grown unilateral adnexal mass, pathologists reported a primary ovarian leiomyoma with no genuine ovarian tissue. This rare diagnosis is found in less than 100 reports after systematic literature review, a greater number of asymptomatic ovarian leiomyomas can be expected. Thorough preoperative diagnostic measures are essential as rare cases of malignancy have been described.

Current trends in diagnostic and therapeutic management of the axilla in breast cancer patients receiving neoadjuvant therapy: results of the German-wide NOGGO MONITOR 24 survey.

PURPOSE: In the last 2 decades, the optimal management of the axilla in breast cancer patients receiving neoadjuvant chemotherapy (NACT) has been one of the most frequently discussed topics. Little is known about the attitudes of surgeons/radiologists towards new developments such as targeted axillary dissection. Therefore, the NOGGO conducted a survey to evaluate the current approach to axillary management. METHODS: A standardized digital questionnaire was sent out to > 200 departments in Germany between 7/2021 and 5/2022. The survey was supported by EUBREAST. RESULTS: In total, 116 physicians completed the survey. In cN0 patients scheduled to receive NACT, 89% of respondents recommended sentinel lymph node biopsy (SLNB) after NACT. In case of ypN1mi(sn), 44% advised no further therapy, while 31% proposed ALND and 25% axillary irradiation. 64% of respondents recommended a minimally invasive axillary biopsy to cN + patients. TAD was used at the departments of 82% of respondents and was offered to all cN + patients converting to ycN0 by 57% and only to selected patients, usually based on the number of suspicious nodes at time of presentation, by 43%. The most common marking technique was a clip/coil. 67% estimated that the detection rate of their marker was very good or good. CONCLUSION: This survey shows a heterogenous approach towards axillary management in the neoadjuvant setting in Germany. Most respondents follow current guidelines. Since only two-thirds of respondents experienced the detection rate of the marker used at their department as (very) good, future studies should focus on the comparative evaluation of different marking techniques.

Diagnosing Pathologic Complete Response in the Breast After Neoadjuvant Systemic Treatment of Breast Cancer Patients by Minimal Invasive Biopsy: Oral Presentation at the San Antonio Breast Cancer Symposium on Friday, December 13, 2019, Program Number GS5-03.

OBJECTIVE: We evaluated the ability of minimally invasive, image-guided vacuum-assisted biopsy (VAB) to reliably diagnose a pathologic complete response in the breast (pCR-B). SUMMARY BACKGROUND DATA: Neoadjuvant systemic treatment (NST) elicits a pathologic complete response in up to 80% of women with breast cancer. In such cases, breast surgery, the gold standard for confirming pCR-B, may be considered overtreatment. METHODS: This multicenter, prospective trial enrolled 452 women presenting with initial stage 1-3 breast cancer of all biological subtypes. Fifty-four women dropped out; 398 were included in the full analysis. All participants had an imaging-confirmed partial or complete response to NST and underwent study-specific image-guided VAB before guideline-adherent breast surgery. The primary endpoint was the false-negative rate (FNR) of VAB-confirmed pCR-B. RESULTS: Image-guided VAB alone did not detect surgically confirmed residual tumor in 37 of 208 women [FNR, 17.8%; 95% confidence interval (CI), 12.8-23.7%]. Of these 37 women, 12 (32.4%) had residual DCIS only, 20 (54.1%) had minimal residual tumor (<5 mm), and 19 of 25 (76.0%) exhibited invasive cancer cellularity of ≤10%. In 19 of the 37 cases (51.4%), the false-negative result was potentially avoidable. Exploratory analysis showed that performing VAB with the largest needle by volume (7-gauge) resulted in no false-negative results and that combining imaging and image-guided VAB into a single diagnostic test lowered the FNR to 6.2% (95% CI, 3.4%-10.5%). CONCLUSIONS: Image-guided VAB missed residual disease more often than expected. Refinements in procedure and patient selection seem possible and necessary before omitting breast surgery.

Applicability of a semiautomated volumetric approach (5D CNS+™) for detailed antenatal reconstruction of abnormal fetal CNS anatomy.

BACKGROUND: The aim of this study was to evaluate the accuracy and reliability of a semiautomated volumetric approach (5D CNS+™) when examining fetuses with an apparent abnormal anatomy of the central nervous system (CNS). METHODS: Stored 3D volumes extracted from a cohort of > 1.400 consecutive 2nd and 3rd trimester pregnancies (range 15-36 gestational weeks) were analyzed using the semiautomatic software tool 5D CNS+™, enabling detailed reconstruction of nine diagnostic planes of the fetal brain. All 3D data sets were examined and judged for plane accuracy, the need for manual adjustment, and fetal CNS anomalies affecting successful plane reconstruction. RESULTS: Based on our data of 91 fetuses with structural cerebral anomalies, we were able to reveal details of a wide range of CNS anomalies with application of the 5D CNS+™ technique. The corresponding anatomical features and consecutive changes of neighboring structures could be clearly demonstrated. Thus, a profound assessment of the entire altered CNS anatomy could be achieved in nearly all cases. The comparison with matched controls showed a significant difference in volume acquisition (p < 0.001) and in need for manual adjustment (p < 0.001) but not in the drop-out rates (p = 0.677) of both groups. CONCLUSION: 5D CNS+™ is applicable in the majority of cases with brain lesions and constitutes a reliable tool even if the integrity of the fetal CNS is compromised by structural anomalies. Using volume data that were acquired in identical cutting sections needed for conventional biometry allows for detailed anatomic surveys grossly independent of the examiner's experience.

Impact of lymphadenectomy on short- and long-term complications in patients with endometrial cancer.

INTRODUCTION: Early endometrial cancer is primarily treated surgically via hysterectomy, adenectomy and, depending on tumor stage and subtype, lymphadenectomy. Systematic lymph node dissection is known to cause surgical complications. The aim of the present study was to investigate morbidity and mortality rates associated with lymphadenectomy in patients with endometrial cancer who underwent surgery in a routine clinical setting. METHODS: We collected data from 232 patients who were operated for endometrial carcinoma between 2006 and 2018 at the University of Lubeck, Germany. Surgical complications were viewed in relation to surgical risk factors. Additionally, a questionnaire concerning long-term lymphatic complications and survival was completed. Survival was compared between patients who underwent lymphadenectomy (group I) and those who did not (group II). RESULTS: Patients in group I needed revision surgery significantly more often due to postoperative complications (such as lymphoceles) compared to those in group II (p = 0.01). The results indicate more serious complications in patients who underwent a systematic lymphadenectomy and in those with lymph node metastases. 15% of patients who underwent a systematic lymphadenectomy had lymph node metastases. Recurrences occurred in 12.5% of cases and were significantly more frequent in patients who had undergone a lymphadenectomy, even if the lymph nodes were negative (p = 0.02). A comparison of survival data during the follow-up period revealed no significant difference. The study highlighted the need for a better preoperative risk stratification and the avoidance of lymphadenectomy for surgical staging alone.

Intraoperative Ultrasound-Guided Excision of Non-Palpable and Palpable Breast Cancer: Systematic Review and Meta-Analysis.

Wire-guided localization (WGL) is the most frequently used localization technique in non-palpable breast cancer (BC). However, low negative margin rates, patient discomfort, and the possibility of wire dislocation have been discussed as potential disadvantages, and re-operation due to positive margins may increase relapse risk. Intraoperative ultrasound (IOUS)-guided excision allows direct visualization of the lesion and the resection volume and reduces positive margins in palpable and non-palpable tumors. We performed a systematic review on IOUS in breast cancer and 2 meta-analyses of randomized clinical trials (RCTs). In non-palpable BC, 3 RCTs have shown higher negative margin rates in the IOUS arm compared to WGL. Meta-analysis confirmed a significant difference between IOUS and WGL in terms of positive margins favoring IOUS (risk ratio 4.34, p < 0.0001, I2 = 0%). 41 cohort studies including 3291 patients were identified, of which most reported higher negative margin and lower re-operation rates if IOUS was used. In palpable BC, IOUS was compared to palpation-guided excision in 3 RCTs. Meta-analysis showed significantly higher rates of positive margins in the palpation arm (risk ratio 2.84, p = 0.0047, I2 = 0%). In 13 cohort studies including 942 patients with palpable BC, negative margin rates were higher if IOUS was used, and tissue volumes were higher in palpation-guided cohorts in most studies. IOUS is a safe noninvasive technique for the localization of sonographically visible tumors that significantly improves margin rates in palpable and non-palpable BC. Surgeons should be encouraged to acquire ultrasound skills and participate in breast ultrasound training.

Robotic surgery in gynecology: is the future already here?

Robotic-assisted surgery has gained widespread acceptance in the surgical community and appears to be the most rapidly developing sector of minimally invasive surgery. However, robotic surgery has been viewed as a development of, or alternative to, laparoscopic surgery and not necessarily as a superior technology. The advantages of MIS over open surgery apply to robotic-assisted surgery as well. Nevertheless, conflicting data have been published about the advantages and disadvantages of robotic-assisted and laparoscopic surgery. In the last few years, robotic-assisted surgery has been used for various gynecological procedures such as hysterectomy, lymphadenectomy, myomectomy, sacrocolpopexy or endometriosis operations. In the present review, we analyze the current use of robotic-assisted surgery and its efficiency in gynecology. Patient-based outcomes, such as quality of life and outcomes in morbidly obese patients are also addressed. The potential benefits of single-port robotic-assisted surgery are discussed. Most of the studies published so far state that robotic-assisted surgery does not essentially improve the surgical outcome compared to conventional laparoscopic surgery. However, randomized studies are scarce. Ongoing technological progress over the next few years may improve robotic-assisted techniques and thus optimize the patient's treatment.

Severe direct and indirect complications of morcellation after hysterectomy or myomectomy.

INTRODUCTION: Despite the significant advantages of morcellation, it may be associated with severe complications. We aimed to determine both direct and indirect complication rates of morcellation at gynecological laparoscopy. MATERIAL AND METHODS: This multicenter retrospective study included patients traced from 2008 to 2017. We identified women who underwent an operation with the use of electromechanical power morcellation (EMM) or vaginal manual morcellation during laparoscopy. Clinical records, intraoperative-postoperative outcomes were reviewed. RESULTS: We analyzed 1795 patients who underwent laparoscopic supracervical hysterectomy (LASH), total hysterectomy (TLH), or myomectomy (45.5%, 14.2%, and 40.3%, respectively). No severe intraoperative complications associated with morcellation or parasitic leiomyoma were observed. Patients with unexpected sarcoma were detected in five cases (0.28%). Four of them were detected after LASH and one after vaginal manual morcellation following TLH, who had an intraabdominal recurrence and died after 18 months. The patients after LASH underwent secondary laparotomy for staging; no histological dissemination of sarcoma was observed, however two had a recurrence. The five-year survival rate was 80%. CONCLUSIONS: There is a small risk of intraoperative complications or unexpected malignancy following morcellation, provided the surgeon adheres to regular surgical standards. In patients with a normal size uterus, TLH could be preferred over LASH to avoid morcellation.

Lymphadenectomy in endometrial cancer - achieving more with less?

The lymph node status of patients with endometrial cancer is known to be a crucial determinant for the prognosis of the disease. It also provides the indication for further adjuvant treatment. The staging of endometrial cancer by surgery has been a controversial issue for more than 30 years. The significant complication rate after lymphadenectomy and the development of minimally invasive surgery have led to the use of sentinel lymph node (SLN) mapping. In the present review, we present the development of surgical staging procedures in patients with endometrial cancer and summarize the recently expanding body of published literature on the subject. SLN mapping is a safe and accurate technique, especially when indocyanine green is used as a tracer. SLN mapping appears to reduce complication rates as well as costs without affecting the oncologic outcome. Large prospective studies are needed to establish the effects of SLN mapping on the outcome of disease, especially in high-risk patients with endometrial cancer. Furthermore, the need for additional systematic lymphadenectomy prior to adjuvant radio-chemotherapy in patients diagnosed with isolated lymph node metastasis during SLN biopsy must be investigated further. This might pave the way for a new surgical approach in patients with endometrial cancer.

The Effect of Collaborative Reviews of Electronic Patient-Reported Outcomes on the Congruence of Patient- and Clinician-Reported Toxicity in Cancer Patients Receiving Systemic Therapy: Prospective, Multicenter, Observational Clinical Trial.

BACKGROUND: Electronic patient-reported outcomes (ePRO) are a relatively novel form of data and have the potential to improve clinical practice for cancer patients. In this prospective, multicenter, observational clinical trial, efforts were made to demonstrate the reliability of patient-reported symptoms. OBJECTIVE: The primary objective of this study was to assess the level of agreement κ between symptom ratings by physicians and patients via a shared review process in order to determine the future reliability and utility of self-reported electronic symptom monitoring. METHODS: Patients receiving systemic therapy in a (neo-)adjuvant or noncurative intention setting captured ePRO for 52 symptoms over an observational period of 90 days. At 3-week intervals, randomly selected symptoms were reviewed between the patient and physician for congruency on severity of the grading of adverse events according to the Common Terminology Criteria of Adverse Events (CTCAE). The patient-physician agreement for the symptom review was assessed via Cohen kappa (κ), through which the interrater reliability was calculated. Chi-square tests were used to determine whether the patient-reported outcome was different among symptoms, types of cancer, demographics, and physicians' experience. RESULTS: Among the 181 patients (158 women and 23 men; median age 54.4 years), there was a fair scoring agreement (κ=0.24; 95% CI 0.16-0.33) for symptoms that were entered 2 to 4 weeks before the intended review (first rating) and a moderate agreement (κ=0.41; 95% CI 0.34-0.48) for symptoms that were entered within 1 week of the intended review (second rating). However, the level of agreement increased from moderate (first rating, κ=0.43) to substantial (second rating, κ=0.68) for common symptoms of pain, fever, diarrhea, obstipation, nausea, vomiting, and stomatitis. Similar congruency levels of ratings were found for the most frequently entered symptoms (first rating: κ=0.42; second rating: κ=0.65). The symptom with the lowest agreement was hair loss (κ=-0.05). With regard to the latency of symptom entry into the review, hardly any difference was demonstrated between symptoms that were entered from days 1 to 3 and from days 4 to 7 before the intended review (κ=0.40 vs κ=0.39, respectively). In contrast, for symptoms that were entered 15 to 21 days before the intended review, no congruency was demonstrated (κ=-0.15). Congruency levels seemed to be unrelated to the type of cancer, demographics, and physicians' review experience. CONCLUSIONS: The shared monitoring and review of symptoms between patients and clinicians has the potential to improve the understanding of patient self-reporting. Our data indicate that the integration of ePRO into oncological clinical research and continuous clinical practice provides reliable information for self-empowerment and the timely intervention of symptoms. TRIAL REGISTRATION: ClinicalTrials.gov NCT03578731; https://clinicaltrials.gov/ct2/show/NCT03578731.

Heterogenous use of misoprostol for induction of labour: results of an online survey among midwives in German-speaking countries.

PURPOSE: This online survey looked at the experiences and general perceptions of midwives concerning induction of labour and the specific use of misoprostol. METHODS: We published an online questionnaire with 24 questions in German on midwives' experiences and perceptions of different methods of induction of labour. RESULTS: The online survey was answered by 412 midwives between February 2016 and February 2017. At least 20% of the 24 questions were answered in 333 questionnaires, which were included in this analysis. Oral misoprostol was the most common induction method for primipara and for women with a previous vaginal birth and an unfavourable cervix. Apart from alternative methods for induction of labour like castor oil and complementary/alternative methods, oral misoprostol was the preferred method of induction of labour by midwives. Midwives described a wide range of dosage schedules concerning application intervals, starting doses, and the maximum daily dose of misoprostol. Approximately 50% of the participants of this study described prescriptions of more than 200 µg misoprostol daily for induction of labour. CONCLUSION: Misoprostol is widely used in Germany and was one of the three preferred methods of induction of labour among midwives in our study next to castor oil and complementary/alternative methods. The preparation and dosage of misoprostol vary significantly among hospitals and do not adhere to international guidelines. Midwives voiced their concerns about inconsistent indications and heterogenous use of different methods and dosages of induction. They wished for more patience with late-term pregnancies and individualized shared decision-making between pregnant women and obstetricians.

Biologically Active Tissue Factor-Bearing Larger Ectosome-Like Extracellular Vesicles in Malignant Effusions from Ovarian Cancer Patients: Correlation with Incidence of Thrombosis.

The development of malignant effusions such as ascites reflects a massive progression of a malignant disease. In patients with ovarian carcinoma, a high amount of ascites (>500 mL) is an independent negative prognostic marker. The composition and constituents of ascites reflect the inflammatory environment of the underlying tumor. Increased cellular resistance of ascites-derived tumor cells and the development of venous thromboembolic events (VTE) are major risks for these patients, especially in patients with advanced ovarian carcinoma. In this study, we discuss the release of tissue factor-bearing extracellular vesicles (TF+ EVs) from tumor cells into the environment (ascites fluid) and their systemic spreading as a possible causal explanation of the pathologic coagulation status in these patients. We obtained ascites from patients with advanced ovarian carcinoma, collected during surgery or therapeutic paracentesis (n = 20). Larger ectosome-like EVs were isolated using sequential centrifugation, quantified by high-resolution flow cytometry and analyzed using nanoparticle tracking analysis. Furthermore, the pro-coagulant properties (TF activity) of EVs were determined. Compared to published TF activities of EVs from healthy persons, TF activities of EVs derived from ascites of patients with ovarian cancer were very high, with a median of 80 pg/mL. The rate of VTE, as reported in the patient files, was high as well (35%, 7 out of 20). Furthermore, all but one patient with VTE had EV concentrations above the median within their ascetic fluid (p < 0.02). Since VTE continues to be a frequent cause of death in cancer patients, prophylactic antithrombotic treatment might be worth considering in these patients. However, given the risk of bleeding, more clinical data are warranted. Although the study is too small to enable reaching a conclusion on direct clinical implementation, it can well serve as a proof of principle and a rationale to initiate a prospective clinical study with different patient subgroups. We also show ex vivo that these larger ectosome-like EVs induce intracellular ERK phosphorylation and tumor cell migration, which is not directly related to their pro-coagulative potency, but might help to understand why cancer patients with thromboembolic events have a poorer prognosis.

A Question of Timing: 10-year Retrospective Analysis on the Use of Antenatal Steroids for Imminent Preterm Birth.

OBJECTIVE: Antenatal steroids improve the neonatal outcome if they are administered within a therapeutic window of seven days before preterm birth. The aim of this study was to evaluate the timing of antenatal steroids for imminent preterm birth at a single center in Germany. MATERIAL AND METHODS: A 10-year retrospective analysis of 843 preterm births between 24/0 and 33/6 weeks was performed from January 2008 to December 2017 at a German university hospital. We evaluated the timing of antenatal steroids according to the indication for their application. Descriptive statistics and binomial regression were performed to analyze factors influencing the timing of antenatal steroid administration. RESULTS: Of 843 preterm births below 34 weeks included in our study, 752 pregnant women received antenatal steroids (89.2%). Only 301/843 women (35.7%) gave birth within the optimal window of 7 days after antenatal steroids. 91/843 women (10.8%) did not receive steroids. 130/843 women (15.4%) only received one dose, 76/843 (9.0%) gave birth within 8 to 14 days, and 245/843 (29.1%) more than 14 days later. In a binomial regression model, preterm premature rupture of membranes (OR 3.40, 95% CI 1.81 to 6.39, p<0.001), fetal growth restriction (OR 3.27, 95% CI 1.63 to 6.58, p=0.001), and preeclampsia (OR 2.83, 95% CI 1.37 to 5.83, p=0.005) were positively associated with optimal timing. CONCLUSION: Two thirds of women with preterm birth before 34 weeks received antenatal steroids outside the optimal therapeutic window. Further research is needed to achieve an optimal effect of antenatal steroids on neonatal outcome and to reduce untimely as well as unnecessary interventions.

Validation of a semiautomated volumetric approach for fetal neurosonography using 5DCNS+ in clinical data from > 1100 consecutive pregnancies.

OBJECTIVE: The aim of this study was to evaluate the validity of a semiautomated volumetric approach (5DCNS+) for the detailed assessment of the fetal brain in a clinical setting. METHODS: Stored 3D volumes of > 1100 consecutive 2nd and 3rd trimester pregnancies (range 15-36 gestational weeks) were analyzed using a workflow-based volumetric approach 5DCNS+, enabling semiautomated reconstruction of diagnostic planes of the fetal central nervous system (CNS). All 3D data sets were examined for plane accuracy, the need for manual adjustment, and fetal-maternal characteristics affecting successful plane reconstruction. We also examined the potential of these standardized views to give additional information on proper gyration and sulci formation with advancing gestation. RESULTS: Based on our data, we were able to show that gestational age with an OR of 1.085 (95% CI 1.041-1.132) and maternal BMI with an OR of 1.022 (95% CI 1.041-1.054) only had a slight impact on the number of manual adjustments needed to reconstruct the complete volume, while maternal age and fetal position during acquisition (p = 0.260) did not have a significant effect. For the vast majority (958/1019; 94%) of volumes, using 5DCNS+ resulted in proper reconstruction of all nine diagnostic planes. In less than 1% (89/9171 planes) of volumes, the program failed to give sufficient information. 5DCNS+ was able to show the onset and changing appearance of CNS folding in a detailed and timely manner (lateral/parietooccipital sulcus formation seen in < 65% at 16-17 gestational weeks vs. 94.6% at 19 weeks). CONCLUSIONS: The 5DCNS+ method provides a reliable algorithm to produce detailed, 3D volume-based assessments of fetal CNS integrity through a standardized reconstruction of the orthogonal diagnostic planes. The method further gives valid and reproducible information regarding ongoing cortical development retrieved from these volume sets that might aid in earlier in utero recognition of subtle structural CNS anomalies.

Analysis of HPV genotype-specific concordance between EUROArray HPV and HPV 3.5 LCD-Array Kit in cervical samples of 163 patients.

PURPOSE: Human papilloma virus (HPV) as the most common viral infection of the anogenital tract is highly associated with intraepithelial neoplasia and cancer of the cervix and other anogential regions. To date, 15 high-risk (HR-) HPV and 3 probably/possibly HR-HPVs have been found to be associated with cervical cancer. Therefore, a screening especially for HR-HPV by appropriate tests is important for detection of precancerous lesions to prevent cancer. The purpose of this study was to analyze prospectively the concordance of the EUROArray HPV genotyping assay (Euroimmun; EUROArray) and the HPV 3.5 LCD-Array Kit (Chipron; LCD-Array). METHODS: Liquid-based, clinician-collected cervical cytology samples (n = 163) from women undergoing cervical inspection at the dysplasia consultation in the colposcopy clinic at the Medical Center-University of Freiburg, Germany were analyzed. Genotype-specific agreement was assessed by Cohen's kappa statistic and McNemar's P value of significance between proportions. RESULTS: Seventeen of the HR-HPV genotypes included in both assays were detected in 42.3% and 38% of samples by EUROArray and by LCD-Array, respectively; i.e. an agreement of 92.0% and a kappa value of 0.83 could be proven between the EUROArray and the LCD-Array. In 50 of 72 samples, identical HR-HPV genotypes were analyzed (81.9%, κ = 0.47) and genotyping for HPV 16 and/or 18 was highly concordant in both tests (relative agreement 96.3%, κ = 0.88). Detection of any HR-HPV was not significantly different after comparison of EUROArray with LCD-Array. CONCLUSION: Both of the tests showed comparable results for the detection of HPV in cervical specimens and permit these assays to be suitable for routine diagnostics.