Fetal auditory evoked responses to onset of amplitude modulated sounds. A fetal magnetoencephalography (fMEG) study.

The human fetal auditory system is functional around the 25th week of gestational age when the thalamocortical connections are established. Fetal magnetoencephalography (fMEG) provides evidence for fetal auditory brain responses to pure tones and syllables. Fifty-five pregnant women between 31 and 40 weeks of gestation were included in the study. Fetal MEG was recorded during the presentation of an amplitude modulated tone (AM) with a carrier frequency of 500 Hz to the maternal abdomen modulated by low modulation rates (MRs) - 2/s and 4/s, middle MR - 8/s and high MRs - 27/s, 42/s, 78/s and 91/s. The aim was to determine whether the fetal brain responds differently to envelope slopes and intensity change at the onset of the AM sounds. A significant decrease of the response latencies of transient event-related responses (ERR) to high and middle MRs in comparison to the low MRs was observed. The highest fetal response rate was achieved by modulation rates of 2/s, 4/s and 27/s (70%, 57%, and 86%, respectively). Additionally, a maturation effect of the ERR (response latency vs. gestational age) was observed only for 4/s MR. The significant difference between the response latencies to low, middle, and high MRs suggests that still before birth the fetal brain processes the sound slopes at the onset in different integration time-windows, depending on the time for the intensity increase or stimulus power density at the onset, which is a prerequisite for language acquisition.

Comparison of prognostic and predictive impact of genomic or central grade and immunohistochemical subtypes or IHC4 in HR+/HER2- early breast cancer: WSG-AGO EC-Doc Trial.

INTRODUCTION: Potential prognostic and predictive markers in early, intermediate-risk breast cancer (BC) include histological grade, Ki-67, genomic signatures, e.g. genomic grade index (GGI), and intrinsic subtypes. Their prognostic/predictive impact in hormone receptor (HR: ER and/or PR) positive/HER2- BC is controversial. WSG-AGO EC-Doc demonstrated superior event-free survival (EFS) in patients with 1-3 positive lymph node receiving epirubicin/cyclophosphamide-docetaxel (EC-Doc) versus 5-fluoruracil/epirubicin/cyclophosphamide (FEC). METHODS: In a representative trial subset, we quantify concordance among factors used for clinical chemotherapy indication. We investigate the impact of central histology (n = 772), immunohistochemistry for intrinsic subtyping and IHC4, and dichotomous (GG) or continuous (GGI) genomic grade (n = 472) on patient outcome and benefit from taxane chemotherapy, focusing on HR+/HER2- patients (n = 459). RESULTS: Concordance of local grade (LG) with central (CG) or genomic grade was modest. In HR+/HER2- patients, low (GG-1: 16%), equivocal (GG-EQ: 17%), and high (GG-3: 67%) GG were associated with respective 5-year EFS of 100%, 93%, and 85%. GGI was prognostic for EFS within all LG subgroups and within CG3, whereas IHC4 was prognostic only in CG3 tumors.In unselected and HR+/HER2- patients, CG3 and luminal-A-like subtype entered the multivariate EFS model, but not IHC4 or GG. In the whole population, continuous GGI entered the model [hazard ratio (H.R.) of 75th versus 25th = 2.79; P = 0.01], displacing luminal-A-like subtype; within HR+/HER2- (H.R. = 5.36; P < 0.001), GGI was the only remaining prognostic factor.In multivariate interaction analysis (including central and genomic grade), luminal-B-like subtype [HR+ and (Ki-67 ≥20% or HER2+)] was predictive for benefit of EC-Doc versus FEC in unselected but not in HR+/HER2- patients. CONCLUSION: In the WSG-AGO EC-Doc trial for intermediate-risk BC, CG, intrinsic subtype (by IHC), and GG provide prognostic information. Continuous GGI (but not IHC4) adds prognostic information even when IHC subtype and CG are available. Finally, the high interobserver variability for histological grade and the still missing validation of Ki-67 preclude indicating or omitting adjuvant chemotherapy based on these single factors alone. TRIAL REGISTRATION: The WSG-AGO/EC-Doc is registered at ClinicalTrials.gov, NCT02115204.

Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression.

BACKGROUND: Taxane-based adjuvant chemotherapy is standard in node-positive (N+) early breast cancer (BC). The magnitude of benefit in intermediate-risk N+ early BC is still unclear. WSG-AGO epiribicine and cyclophosphamide (EC)-Doc is a large trial evaluating modern taxane-based chemotherapy in patients with 1-3 positive lymph nodes (LNs) only. PATIENTS AND METHODS: A total of 2011 BC patients (18-65 years, pN1) were entered into a randomized phase III trial comparing 4 × E90C600 q3w followed by 4 × docetaxel 100 q3w (n = 1008) with the current standard: 6 × F500E100C500 q3w (n = 828) or C600M40F600 d1, 8× q4w (n = 175). Primary end point was event-free survival (EFS); secondary end points were overall survival (OS), toxicity, translational research, and quality of life. Central tumor bank samples were evaluable in a representative collective (n = 772; 40%). Ki-67 was assessed centrally in hormone receptor-positive disease as a surrogate marker for the distinction of luminal A/B-like tumors. RESULTS: Baseline characteristics were well balanced between study arms in both main study and central tumor bank subset. At 59-month median follow-up, superior efficacy of EC-Doc [versus FEC (a combination of 5-fluorouracil, epirubicin, and cyclophosphamide)] was seen in EFS and OS: 5-year EFS: 89.8% versus 87.3% (P = 0.038); 5-year OS: 94.5% versus 92.8% (P = 0.034); both tests one-tailed. EC-Doc caused more toxicity. In hormone receptor-positive (HR)+ disease, only high-Ki-67 tumors (≥ 20%) derived significant benefit from taxane-based therapy: hazard ratio = 0.39 (95% CI 0.18-0.82) for EC-Doc versus FEC (test for interaction; P = 0.01). CONCLUSION: EC-Doc significantly improved EFS and OS versus FEC in intermediate-risk BC (1-3 LNs) within all subgroups as defined by local pathology. In HR+ disease, patients with luminal A-like tumors may be potentially over-treated by taxane-based chemotherapy. CLINICAL TRIAL NUMBER: ClinicalTrials.gov, NCT02115204.

Impaired bone microenvironment: correlation between bone density and presence of disseminated tumor cells.

BACKGROUND: Disseminated tumor cells (DTCs) in bone marrow (BM) occur in 30-40% of primary breast cancer patients. An impaired bone microenvironment may lead to reduced bone density and osteoporosis affecting the BM as a homing site for DTCs. The bone mineral density (BMD) and its correlation to DTC in BM was evaluated. MATERIALS AND METHODS: One hundred and eighty-one women (70 premenopausal, 111 postmenopausal) underwent quantitative ultrasonometry before adjuvant chemotherapy. BM aspirates were analyzed by immunocytochemistry using the ACIS system (Chromavision) based on immunostaining. RESULTS: DTCs were detected in 39% of the patients. Positive BM status correlated significantly with the nodal status. BMD was significantly reduced in the postmenopausal patients (p=0.003). Smaller tumors and higher BMD correlated significantly (p<0.014). Fifty percent of the patients with preclinical osteoporosis were BM positive, whereas 37% with normal or osteopenic BMD had DTCs. CONCLUSION: An impaired bone micro-environment as found in preclinical osteoporosis might be a homing site for DTCs.

Breast cancer patients' expectations in respect of the physician-patient relationship and treatment management results of a survey of 617 patients.

BACKGROUND: The following study was conducted to explore patients' information needs and preferences with a special focus on doctor-patient communication. PATIENTS AND METHODS: A 62-item questionnaire developed by a multidisciplinary team and validated in a phase-I study was given to breast cancer patients via the Internet (homepage) or in a hard copy version. RESULTS: A total of 617 patients responded, 552 on line and 65 via the hard copy questionnaire. The median age of the on-line group was 47 (21-85) and 55 (40-92) in the hard copy group. Sixty-five per cent of the patients were treated with the intention of achieving a cure and 35% of the patients had metastatic disease. The median length of the consultation communicating the information 'You have breast cancer' was 15 min (0-300). The most effective and patient-relevant source of information about the disease and the treatment options was consultation with the physician (84%). When asked to suggest areas for improvement, patients' most common answers were: more complementary therapies should be offered by the physician (54%); physicians should take more time to explain things (51%); and cooperation between the physicians involved in the patient's care should be improved (39%). The questions most relevant to patients were: 'Am I getting the right therapy?' (89%); 'How many patients with my condition does my doctor treat?' (46%) and 'Can I be enrolled into a trial?' (46%). An independent second opinion centre was desired by 94% of the respondents but only 20% knew of any such resource. CONCLUSIONS: This study underlines the need to give patients with breast cancer the full details on treatment options and cancer management. The results provide a suitable basis for a broader interdisciplinary discussion of the patient-physician relationship and should be useful in generating hypotheses for subsequent prospective studies.

Class-specific pro-apoptotic effect of statins on human vascular endothelial cells.

Neonangiogenesis represents an important step in tumor development and propagation. Statins may have anticancerogenic potential by blocking vascular endothelial cell growth. The antiproliferative effect of four statins on human endothelial cells was compared, concomitantly delineating a possible pro-apoptotic process. All four statins tested, i. e. atorvastatin, fluvastatin, lovastatin, and simvastatin inhibited cell proliferation. Nearly complete blocking of cell proliferation was achieved at a concentration of 10 microM. We were able to demonstrate that the antiproliferative effect of the statins is not due to cytotoxicity but rather to an apoptotic effect as demonstrated by comparison of cytotoxicity assay and apoptosis assay. The apoptotic mechanism seems to involve caspases, since the statins significantly enhanced caspase activity at dosages of 10 and 20 microM. Further experiments revealed a downregulation of the pro-apoptotic protein Bcl-2. Our data indicate that statins may class-specific inhibit angiogenesis at high dosages which can contribute to prevention of tumor development and progression.

Local and systemic tolerability of magnesium sulphate for tocolysis.

An open-label, randomised, parallel-group, study was conducted in three study centres in women with premature labor and indication for a single agent intravenous tocolysis therapy with magnesium sulphate. The aim of this study was to examine the local and general tolerability and side-effects of magnesium sulphate for tocolysis. Furthermore, we tested the tolerability of a ready-for-use magnesium solution. No measurements of efficacy were performed during this study. Initially, patients received a loading dose of 4.0 g magnesium sulphate administered over 30 min. Thereafter, a continuous intravenous infusion of 1-2 g magnesium sulphate per hour up to 21 days was given. Venous score (Maddox), vital signs, adverse events as well as general tolerability (assessed by investigator and patients) and blood parameters were assessed. We showed good local and systemic tolerability of high dose magnesium sulphate for tocolysis. Only seven patients (15%) were withdrawn from the study prematurely due to minor adverse events. Potential serious complications of MgSO(4) such as respiratory arrest or clinically relevant respiratory depression were not observed. The most frequently reported local adverse events were injection site pain, itching, erythema, swelling, induration and palpable venous cord. The most common systemic adverse events considered to be possibly related to the study drugs involved the nervous system (dizziness) followed by the digestive system (nausea, constipation). Systolic and diastolic blood pressure changed only slightly during the treatment. Respiratory rate and body temperature remained stable also. Toxic magnesium levels (>2.5 mmol/l) were not observed. The assessment of the clinical investigators with regard to tolerability was very good or good in 72.5% of the patients. The introduction of the ready-to-use solution has the advantage of eliminating the need to mix the solution prior to administration. This means a lower risk of overdose and contamination.

Additive antioxidative effect of hormone replacement therapy combined with a statin.

In treating postmenopausal women both statins and estrogens have been shown to elicit favourable effects on lipids and lipoproteins. In addition direct beneficial effects of these substances on the vascular wall are discussed. However, progestin addition to estrogen replacement therapy, which is mandatory in women with an intact uterus. is thought to deteriorate at least partly estradiol-induced direct effects on the vasculature. Oxidation of LDL, which mainly takes place in the vessel wall, seems to be a crucial step in the development of atherosclerosis. Therefore, for the first time, the effect of a statin and an estrogen/progestin combination on the in vitro oxidation of human LDL was investigated comparing the monosubstances fluvastatin. 17beta-estradiol and norethisterone acetate (NETA) as well as the effect of the combination. LDL was isolated from human female serum and oxidation was initiated by copper(II)-chloride. The progression of LDL oxidation was monitored spectrometrically at 234 nm for 300 min. Fluvastatin significantly delayed the onset of LDL oxidation (controls = 85 min) by 21 min at 1 microM, by 99 min and by 210 min at 5 and 10 microM. respectively. 17beta-estradiol significantly reduced the onset by 73 min at 1 microM and by more than 300 min at 5 and 10 microM. NETA had no significant effect. The combination of I microM 17beta-estradiol and 1 microM fluvastatin with 1, 5 and 10 microM NETA showed an additive antioxidative effect of estradiol and fluvastatin and no deterioration by the addition of NETA even at high dosages. It can be concluded that treatment of postmenopausal women with fluvastatin and a combination of 17beta-estradiol with NETA may have not only beneficial effects on lipid disorders but may also elicit a direct potent antiatherosclerotic action on the vasculature.

Multifibre Application in Laser-Induced Interstitial Thermotherapy under On-Line MR Control.

.The application of multiple fibres for the conformal irradiation of tumours by laser-induced interstitial thermotherapy (LITT) has been investigated. A study was performed to evaluate the coagulated zones produced in porcine muscle tissue in vitro. For delivering specified powers into the tissue, a multifibre system was developed which allows the simultaneous use of up to four fibres. A new quantitative method of magnetic resonance imaging (MRI) has been applied for real-time thermometry. It is based on the temperature dependence of the T1 relaxation time and the equilibrium magnetisation. The MR results were compared with the measurements of fibreoptic thermometers. Since the acquisition time of the selected MR sequence takes only 3 s per slice and the calculation of the temperature measurement could be realised within a few seconds, the temperature mapping works closely to real time. The accuracy of the temperature measurements in muscle tissue was 1.5°C. Whereas single-fibre applications induced convex-shaped isotherms, concave structures were generated by a multifibre LITT.

Treatment of the twin-twin transfusion syndrome: initial experience using laser-induced interstitial thermotherapy.

This paper describes our initial experience with laser-induced interstitial thermotherapy (LITT) for the treatment of the twin-twin transfusion syndrome (TTTS). This procedure was utilized in four pregnancies-three monochorionic twin pregnancies and one triplet pregnancy (20-26 weeks of gestation)-with severe TTTS with fetal dropsy, polyhydramnion of the acceptor, and anhydramnion of the donor. In vitro examinations of placental tissue had shown that laser coagulation can be monitored by sonography, hence we used this method for the first time in these four pregnancies. Blood vessels connecting the two umbilical cords were determined prior to the treatment using a new ultrasound color technique which is highly sensitive and capable of representing slow blood flow velocities. A 1.2 mm thick puncture needle was then directed to the shunt under on-line ultrasound control. All patients had an anterior wall placenta. The laser fiber was inserted via this thin needle. A coagulation time of 2-3 min was necessary at 3 W. In the one twin pregnancy the intrauterine fetal death of the smaller child occurred 10 weeks after LITT, the other child survived and is healthy. A cesarian section was necessary in another twin pregnancy 1 week after LITT due to the intrauterine death of the smaller child. In the third twin pregnancy, the donor, who had already had distinct bradycardia prior to the treatment, died immediately after LITT. The intrauterine fetal death of the donor in the triplet pregnancy occurred 3 days after LITT once the volume of amniotic fluid had basically returned to normal. The tragic intrauterine death of the uninvolved child occurred 13 weeks later as a result of umbilical cord strangulation, the surviving child is healthy. All four pregnancies were severe and advanced cases of TTTS with a very poor prognosis, leaving us with no other alternative to the described method of treatment. The instruments we used are a lot thinner than those utilized for fetoscopic laser treatment to date. Furthermore, it is not necessary to penetrate the amniotic sac in patients with an anterior wall placenta; intraplacental vessels can be coagulated, and the laser energy required for LITT is also much lower. In our opinion these advantages justify the utilization of LITT under more promising conditions than those described above.