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

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

[Umbilical Absent and Reverse End-Diastolic Flow Velocity Waveforms Already Present Prior to Viability do not Exclude Long-Term Foetal Surveillance: A Report of Two Cases]. / Langzeitüberwachung nach dopplersonografischem Nachweis eines umbilikalen Null- und Rückflusses vor extrauteriner Lebensfähigkeit - 2 Kasuistiken.

The finding of absent or reverse end-diastolic flow velocities (AREDV) in the umbilical artery already prior to viability corresponds to the most severe end of the clinical spectrum of placental insufficiency. However, there is little or no experience or published literature with regard to perinatal outcome. We report 2 cases in which structurally and chromosomally normal foetuses showed severe early onset retardation but were continuing to grow. These gestations could be prolonged by 62 and 64 days, respectively. Perinatal outcome was good in both following Caesarean section at 32+3 and 31+5 gestational weeks respectively.

[Prognostic factors of perinatal short-term outcome in severe placental insufficiency using Doppler sonography to assess end-diastolic absent and reverse blood flow in umbilical arteries]. / Prognosefaktoren des perinatalen Kurzzeitergebnisses bei schwerer Plazentainsuffizienz mit dopplersonografisch enddiastolischem Null- und Rückfluss in der Art. umbilicalis.

Significant placental insufficiency, indicated by Doppler ultrasound findings of absent or reverse end-diastolic flow velocities (AREDV), is associated with increased morbidity and mortality. Analysis of blood flow in the ductus venosus should assist in early intrauterine recognition of threatened foetuses. 58 high-risk pregnancies with umbilical AREDV were repeatedly examined (n=364). Doppler findings were correlated with neonatal signs of deterioration (ratio of normoblasts to leukocytes, pH, base excess, Apgar score), as well as short-term morbidity [need for intubation, duration of assisted respiration, evidence of respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), necrotising enterocolitis (NEC), intraventricular haemorrhage (IVH grade III+IV)] against the analysis of the blood flow findings (normal or increased pulsitility, absence or reverse end-diastolic flow) in the umbilical arteries (AU), the middle cerebral arteries (ACM) and ductus venosus (DV) relating these to birth weight and the duration of the pregnancy. The median period of observation was 12.8 days, 48% of the foetuses showed an abnormal ductus venosus flow and 26% an absent venous or reverse end-diastolic flow. The median date of delivery was 30 weeks, with a mean birth weight of 816 g. 93% were live births with 12% dying postnatally. Although the criteria for postnatal morbidity (BPD, NEC, IVH III+IV) and mortality did not correlate with changes in arterial and venous Doppler parameters in our group, there was a significant relationship between the normoblast count, known to be a marker of chronic hypoxia. The Apgar 10 minte score, umbilical arterial pH and base excess were correlated with changes in the DV flow curves. Healthy survival started, irrespective of arterial or venous blood flow criteria, from 27+0 weeks of pregnancy. If born between 27.0 and 30+6 weeks, the infants were more likely to be healthy the less the blood flow had been compromised. A birth weight of 590 g (sensitivity 62.5%; specificity 93.5%) and gestational age of 28+5 weeks (sensitivity 87.5%; specificity 90.3%) were shown to be cut-off points between healthy survival and survival with serious neonatal complications.

[Ductus venosus blood flow prior to intrauterine foetal death in severe placental insufficiency can be unaffected as shown by doppler sonography]. / Die Ductus venosus Dopplerflusskurve vor intrauterinem Fruchttod bei schwerer Plazentainsuffizienz mit dopplersono-grafisch enddiastolischem Null- und Rückfluss in der Art. Umbilicalis.

Significant placental insufficiency with Doppler ultrasound findings of absent or reverse end-diastolic flow velocities (AREDV) is associated with increased morbidity and mortality. An analysis of blood flow in the ductus venosus assists in the early recognition of threatened foetuses. However, the prognostic value of multivessel Doppler assessment for the timing of delivery is being questioned. Four high-risk pregnancies with umbilical AREDV were repeatedly examined prior to intrauterine foetal demise. Our results demonstrate that ductus venosus Doppler flow velocimetry can be normal prior to intrauterine foetal death.

[Myocardial infarction in the 34th week of gestation: case report]. / Myokardinfarkt in der 34. Schwangerschaftswoche.

Acute myocardial infarction during pregnancy is a rare event that is often associated with a very high maternal mortality, estimated to be from 19 to 37%. During the last decades the incidence of myocardial infarction during pregnancy has increased . The main contributing factor could be a higher prevalence of the metabolic syndrome. The strongest predictors correlated with a myocardial infarction are hypertension, diabetes mellitus and advanced maternal age. In addition, improved diagnostic tools could explain the elevated incidence of myocardial infarction during pregnancy. In general gestation is not considered a risk factor for myocardial infarction but gravidity is accompanied by an increase in oestrogen and progesterone levels. It is generally accepted that oral contraceptives increase the risk of coronary heart disease. We present a case where a 37-year-old gravida was admitted to hospital with diffuse thoracic pain. In the patient's history, we found several putative reasons for the thoracic pain that pointed to a musculoskeletal cause. Based on an elevation of ischaemic heart markers and continuous non-specific thoracic pain we performed a primary Cesarean section. In the coronary angiography procedure that followed, a thrombotic occlusion of the ramus diagonalis was diagnosed. We here describe the differential diagnosis as well as the problems associated with diagnosing myocardial infarction in the third trimester of pregnancy.

[Obstetric analgesia in German clinics. Remifentanil as alternative to regional analgesia]. / Geburtshilfliche Analgesie in deutschen Kliniken. Remifentanil als Alternative zur Regionalanalgesie.

OBJECTIVE: Epidural regional analgesia is still recommended as the gold standard for obstetric analgesia due to its high efficacy and less depressing effects to the central nervous system. However, if absolute or relative contraindications for a regional anesthetic technique are present, there is a need for an effective and safe alternative. This survey investigates the current use of intravenous opioids, with a focus on remifentanil as patient-controlled intravenous analgesia (PCIA), in obstetrics in German hospitals. METHODS: A questionnaire was sent to 930 anesthesia units. Data were collected and analyzed using SPSS statistical package (PASW Statistics 18.0). The questionnaire requested statistics on births, the existing alternative labor analgesic techniques, intramuscular or intravenous opioids, PCIA or other options. Furthermore, the questions focused on details regarding the use of intravenous opioids in conjunction with PCIA techniques. RESULTS: Replies were received from 343 anesthetic departments (response rate 37%) and 281 clinics had an obstetric department and were included for further analysis. All clinics provided a 24 h epidural service and the most commonly used opioids were pethidine (19%), meptazinol (17%) and piritramide (16%) for intermittent intravenous/intramuscular administration. Only 0.9% of the clinics offered nitrous oxide as an alternative analgesic technique and 22 (8%) of the responding anesthetic departments offered PCIA. Remifentanil was the most popular choice in conjunction with PCIA (68%) for labor analgesia. Most hospitals offering PCIA continuously monitor oxygen saturation (91%) and the blood pressure (95%), whereas continuous electrocardiograms (18%) and clinical observation of the respiratory frequency (19%) were less commonly reported. However, most clinics offered one-to-one nursing for the parturient using an opioid PCIA. CONCLUSIONS: This survey revealed that pethidine, meptazinol and piritramide are the most common opioids for opioid-based systemic labor pain relief in Germany. If PCIA is offered, remifentanil is the most popular opioid. However, only a few clinics are routinely using PCIA for obstetric analgesia. Furthermore the study showed that the current monitoring standards seem to have room for improvement with respect to safe administration of an opioid PCIA. The safety standards require continuous observation of the oxygen saturation, the possibility for oxygen supply, one-to-one nursing for a close clinical observation of the mother and the presence of an anesthetist during the initial titration phase to safely apply this technique. Applying these safety standards PCIA may prove a useful alternative for central neuraxial labor analgesia in those women who either do not want, cannot have or do not need epidural analgesia.

[Patient-controlled intravenous analgesia with remifentanil as an alternative to epidural analgesia during labor: case series and discussion of medicolegal aspects]. / Remifentanil zur geburtshilflichen Schmerzerleichterung per patientenkontrolliertem Analgesieverfahren: Fallserie und Diskussion medikolegaler Aspekte.

BACKGROUND: Epidural analgesia is considered as the standard method for labor analgesia by inducing a minimal negative impact on labor while providing effective analgesia. Labor analgesia in the absence of epidural analgesia is difficult to achieve with the commonly used analgesic interventions. If epidural analgesia is not feasible due to coagulation disorders, anticoagulation, inability to insert an epidural catheter or due to the mother''s refusal to accept neuraxial analgesia, there is a need for interventions to cope with labor pain. So far, pethidine, diamorphine, meptazinol and spasmolytics remain the most widely used substances for IM and IV use. Unfortunately, in addition to not being very effective, these interventions may be associated with undesirable side effects for the parturient and the newborn. For a decade, anaesthesiologists have experienced the unique properties of remifentanil in the settings of surgical anaesthesia and conscious sedation since it was introduced for labor analgesia. Unfortunately, remifentanil is not licensed for administration to the pregnant patient, and it is unlikely that the manufacturers would consider the cost justified. METHODS: Therefore, relevant concerns, legal issues and precautions are discussed based on the presentation of case series and a protocol is presented on how the use of remifentanil can be safely implemented for labor analgesia in selected situations. RESULTS AND CONCLUSIONS: Proper informed consent, appropriate monitoring for the mother and the newborn, one-to-one nursing or midwifery care as well as the availability of an attending physician experienced in neonatal resuscitation and an anaesthesiologist with experience regarding the use of remifentanil are important to ensure that this method retains its good reputation for obstetric analgesia.

[Neonatal results of prgenancies in overweight and obese mothers at the University of Würzburg Gynaecology Clinic--a comparison of the years 1980 and 2005]. / Neonatales Ergebnis von Schwangerschaften übergewichtiger und adipöser Mütter an der Universitäts-Frauenklinik Würzburg - ein Vergleich zwischen 1980 und 2005.

BACKGROUND: The prevalence of overweight and obesity in pregnant women has increased during the last decades (in our examination period from 10.9 to 29.8 %). Maternal obesity is a risk factor for pregnancy, delivery and the newborn. Does the neonatal outcome of pregnancies with maternal overweight and obesity in 2005 differ from that in 1980? METHODS: All patients with a body mass index (BMI) > 25 kg / m (2) who delivered in 1980 (n = 130) and in 2005 (n = 392) at the University Hospital Würzburg were evaluated retrospectively. The neonatal result of singletons born at term was studied (1980: n = 125; 2005: n = 315). RESULTS: The rates of macrosomia > 4500 g (5.6 vs. 1.3 %) and shoulder dystocia (4.8 vs. 0.3 %) declined significantly. No significant differences were found regarding the mean newborn weight (3560 vs. 3508 g), weight percentile (55.5 vs. 56.4 %), length (51 cm), head size (35 cm), fetal distress (3.2 vs. 3.8 %), respiratory insufficiency (3.2 vs. 2.2 %), 5-min-Apgar (9.77 vs. 9.69) and arterial umbilical cord pH (7.27 vs. 7.26). Birth weight was not associated with the degree of obesity in 2005 compared to 1980. CONCLUSION: Despite the increasing prevalence and severity of obesity in pregnant women most parameters of neonatal outcome did not change. The observed relative rate of macrosomia and shoulder dystocia declined, but the case number of these complications is still relevant. Obviously obstetricians have responded appropriately to the changing risk profile.

A case of metastasizing invasive hydatidiform mole. Is less--less good? Review of the literature with regard to adequate treatment.

BACKGROUND: Patients with invasive hydatidiform moles (IHM) have a good prognosis. Even if disease has spread, monocytostatic treatment might be sufficient if the diagnosis has been histologically confirmed. Established classifications divide gestational trophoblastic disease (GTD) including choriocarcinoma into cases with "high" and "low" risk. Without respect to histology "high-risk" cases are recommended to obtain polychemotherapy. CASE: A 40-year-old nullipara underwent hysterectomy for persistent vaginal bleeding after she had already been treated with curettage for hydatidiform mole. An IHM was pathohistologically confirmed. There were no signs of pulmonary spread or other metastases at the time of surgery. Postsurgically persistent beta-hCG levels lead to thorough staging, which revealed multiple pulmonary metastases and a vaginal metastasis. Despite metastasizing GTD with poor prognosis criteria she was treated with single agent therapy. Eight cycles of two weekly methotrexate (MTX) were administered. All sites of metastases responded and our patient is still fine after one year of follow-up. CONCLUSION: With respect to this and other reports monochemotherapy can be a reasonable primary treatment for metastatic IHM.

Estrogen-dependent rapid activation of protein kinase C in estrogen receptor-positive MCF-7 breast cancer cells and estrogen receptor-negative HCC38 cells is membrane-mediated and inhibited by tamoxifen.

We examined protein kinase C (PKC) in the regulation of breast cancer cells by estrogen. Estrogen receptor (ER)- positive (+) MCF-7 and ER-negative (-) HCC38 cells were treated with 17 beta-estradiol (E(2)) or E(2)-BSA, which cannot enter the cell. E(2) and E(2)-BSA rapidly increased PKC-alpha in both cells via phosphatidylinositol-dependent phospholipase C and G protein, but not phospholipase A(2) or arachidonic acid. In MCF-7 cells, E(2) and E(2)-BSA had comparable effects, maximal at 90 min. In HCC38 cells, PKC was maximal at 9 min, with E(2)-BSA more than E(2). Tamoxifen blocked estrogen-dependent PKC in MCF-7 cells and reduced it in HCC38 cells. ER-antagonist ICI 182780, ER-agonist diethylstilbestrol, and antibodies to ER alpha and ER beta had no effect. E(2) stimulated [(3)H]thymidine incorporation in MCF-7 only; E(2)-BSA had no effect. Tamoxifen did not alter E(2)-dependent increases in MCF-7 cells, whereas ICI 182780 reduced DNA synthesis in control and E(2)-treated cultures. PKC activity was positively correlated with tumor severity in 133 breast cancer specimens and was greater in ER(-) tumors. Tamoxifen treatment reduced recurrence, and recurrent tumors had higher PKC activity. This indicates that E(2) rapidly increases PKC activity via membrane pathways not involving ER alpha or ER beta and suggests that tamoxifen works by reducing PKC activity through non-ER alpha/ER beta-dependent mechanisms.