Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)†.

BACKGROUND: The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline-taxane-based neoadjuvant chemotherapy increases pathological complete response (pCR) rates overall and specifically in patients with triple-negative breast cancer (TNBC). No difference in pCR rate was observed for adding everolimus to paclitaxel in nonearly responding patients. Here, we present disease-free (DFS) and overall survival (OS) analyses. PATIENTS AND METHODS: Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel (EC-T) with or without eight infusions of bevacizumab every 3 weeks before surgery. Patients without clinical response to EC ± Bevacizumab were randomized to 12 weekly cycles paclitaxel with or without everolimus 5 mg/day. To detect a hazard ratio (HR) of 0.75 (α = 0.05, ß = 0.8) 379 events had to be observed in the bevacizumab arms. RESULTS: With a median follow-up of 3.8 years, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.784 for DFS and HR 0.974; P = 0.842 for OS) compared with patients receiving chemotherapy alone. Patients with TNBC similarly showed no improvement in DFS (HR = 0.99; P = 0.941) and OS (HR = 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1-3 or cT4; pCR or not) showed a significant benefit. No difference in DFS (HR 0.997; P = 0.987) and OS (HR 1.11; P = 0.658) was observed for nonearly responding patients receiving paclitaxel with or without everolimus overall as well as in subgroups. CONCLUSIONS: Long-term results, in opposite to the results of pCR, do not support the neoadjuvant use of bevacizumab in addition to an anthracycline-taxane-based chemotherapy or everolimus in addition to paclitaxel for nonearly responding patients. CLINICAL TRIAL NUMBER: NCT 00567554, www.clinicaltrials.gov.

[Late preterms: the influence of foetal gender on neonatal outcome]. / Late preterms: Auswirkungen des fetalen Geschlechts auf das neonatologische Outcome.

BACKGROUND: The group of the so-called late preterms (infants born at 34 0/7-36 6/7 weeks gestational age) has been underestimated with respect to their neonatal outcome. Among infants born before the 29th week of pregnancy, a gender-specific difference in favour of females regarding morbidity became evident. The aim of this study is to investigate whether these findings are transferable to the group of late preterms. METHODS: The neonatal outcome of 528 consecutive singletons, born at 34 0/7-36 6/7 weeks gestational age and requiring intensive care, was examined. RESULTS: Neonatal complications have been particularly analysed with regard to gender-specific differences. Boys (n=292) were significantly more frequently affected by sepsis (3.8 vs. 0.9%; p=0,0314, x²-test). Girls had significantly longer stays in the neonatal intensive care unit (median 12 (Q1:8; Q3:17) vs. 11 (6;16) days; p=0.0149, t-test). In a multiple logistic regression model, male gender and premature rupture of membranes were borderline significant with respect to the occurrence of sepsis - boys had a 4.4-fold risk (OR=0.228 [95% CI: 0.050-1.041]; p=0.0564) and premature rupture of membranes had a 3.5-fold risk (OR=3.462 [0.938-12.779]; p=0.0623). Strong cause variables for the length of stay in the neonatal intensive care unit were birth weight, gestational age and premature rupture of membranes after adjustment. CONCLUSION: The influence of foetal gender on the neonatal outcome in the late preterm group (34 0/7-36 6/7 gestational age) has been relativised.

PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel and CMF versus a standard-dosed epirubicin/cyclophosphamide followed by paclitaxel ± darbepoetin alfa in primary breast cancer--results at the time of surgery.

BACKGROUND: Preoperative chemotherapy is a recommended treatment of both primary operable and locally advanced breast cancer. Strategies to improve efficacy include the use of anthracyclines, taxanes, and intensified dose with bone marrow support. PATIENTS AND METHODS: Patients received neoadjuvant epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) followed by paclitaxel 175 mg/m(2) (EC→T), each 3-weekly for four cycles (n = 370), or epirubicin 150 mg/m(2) followed by paclitaxel 225 mg/m(2) with pegfilgrastim followed by CMF (cyclophosphamide 500 mg/m(2), methotrexate 40 mg/m(2), fluorouracil 600 mg/m(2)) on days 1 and 8 (E(dd)→T(dd)→CMF), each 2-weekly and for three cycles (n = 363). Patients were randomly allocated to either simultaneous darbepoetin alfa (DA) (n = 356) or none (n = 377). RESULTS: Pathological complete response (pCR) rate (breast) was higher with E(dd)→T(dd)→CMF, 18.7% versus 13.2% with EC→T; P = 0.043, ypT0/Tis; ypN0 was reported in 20.9% versus 14.3% respectively; P = 0.019. Patients with grade 3 tumors and negative hormone receptor status had a significantly higher pCR rate. Mean hemoglobin values maintained higher with DA (13.6 versus 12.6 g/dl). E(dd)→T(dd)→CMF regimen showed more grade 3-4 mucositis, sensory neuropathy, and neurological complaints. Thromboembolic events were more frequent on DA (3% versus 6%; P = 0.055). CONCLUSION: Dose-dense and -intensified neoadjuvant chemotherapy with E(dd)→T(dd)→CMF was potentially superior to EC→T in terms of pCR. Primary use of DA did not affect pCR.

PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel, and CMF versus a standard-dosed epirubicin-cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer--outcome on prognosis.

BACKGROUND: The objective of this study was to compare the effect of dose-intensified neoadjuvant chemotherapy with that of standard epirubicin plus cyclophosphamide followed by paclitaxel in combination with or without darbepoetin on survival in primary breast cancer. PATIENTS AND METHODS: A total of 733 patients received either four cycles of neoadjuvant epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks followed by four cycles of paclitaxel 175 mg/m(2) every 3 weeks (EC→T), or three cycles of epirubicin 150 mg/m(2) every 2 weeks followed by three cycles of paclitaxel 225 mg/m(2) every 2 weeks followed by three cycles of combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (E(dd)→T(dd)→CMF). The patients were randomly assigned to receive darbepoetin or none. The primary objective was to demonstrate a superior disease-free survival (DFS) of E(dd)→T(dd)→CMF compared with EC→T. RESULTS: Estimated 3-year DFS was 75.8% with EC→T versus 78.8% with E(dd)→T(dd)→CMF [hazard ratio (HR) 1.14; P = 0.37] and overall survival (OS) 88.4% versus 91.5% (HR 1.26; P = 0.237). Three-year DFS was 74.3% with darbepoetin versus 80.0% without (HR 1.31; P = 0.061) and OS 88.0% versus 91.8% (HR 1.33; P = 0.139). Patients with a pathologically documented complete response [pathological complete response (pCR)] had a significantly better DFS compared with those without achieving a pCR (estimated 3-year DFS: 89.2% versus 74.9%; HR 2.27; P = 0.001). CONCLUSION: Neoadjuvant dose-intensified chemotherapy compared with standard chemotherapy did not improve DFS, whereas the addition of darbepoetin might have detrimental effects on DFS.

[The endocrinological aspects of the therapy of testicular involvement in children with acute leukemias]. / Endokrinologische Aspekte zur Therapie des Hodenbefalls bei Kindern mit akuten Leukämien.

Orchidectomy or testicular irradiation with 24 to 30 Gy are recommended for testicular involvement in boys with acute lymphoblastic leukemia. But, recommended radiation doses for the only occultly involved other testis differ, i.e. they range from 12 to 24 Gy. Low dose (12 or 15 Gy) "preventive" testicular irradiation was delivered to 5 of 14 patients; only one of these 5 experienced a further testicular relapse. According to our observation, in contrast to higher doses, the dose limitation allows spontaneous pubertal development including normal testosterone production and normal development of the masculine stature.

[Changes in the psychosomatic status following operative augmentation and reduction of the female breast. Catamnestic study from the operative-gynecologic and psychosomatic viewpoints]. / Anderung der psychosomatischen Situation nach operativer Augmentation und Reduktion der weiblichen Brust. Katamnestische Untersuchung aus operativ-gynäkologischer und psychosomatischer Sicht.

We performed preoperatively a psychiatric and psychosomatic exploration of women who came to us with a request for performing breast-corrective surgery. 18 months after the operation, these women were again examined both gynaecologically and psychosomatically. Subsequent to a postoperative course without complications and with primary wound healing, 88% of the surgically treated women considered the result to be in accordance with their expectations, and the size of their breast as adequate. Analysis of variance of the personality data reveals that patients with hypoplasia or hyperplasia of the breast do not differ from each other in respect of their personality characteristics. Preoperatively, the patients assessed themselves on the average very negatively with regard to social resonance, and proved to be very depressive. After plastic surgery of the breast, i.e. after anatomic correction, definite changes are seen in the mental field. A significant improvement is noticeable in the way the patients experience themselves, their body, and their self-value. The same also applies to the experience of their sexuality, to social relationships and social resonance, social potency, and partner relationship. All these were assessed by the patients as considerably improved (significant on the 1% level).

[Changes in erythrocyte P50 and its effect on O2 transport in intravenous tocolysis with fenoterol (Partusisten)]. / Veränderungen des erythrozytären P50 und seines Einflusses auf den O2-Transport unter intravenöser Tokolyse mit Fenoterol (Partusisten).

Fenoterol (Partusisten), which has a considerable influence on glucose metabolism in addition to its well-known cardiac side-effects, does not appear to have any direct influence on the P50 of the maternal erythrocytes in in-vitro experiments. In incubation experiments with fresh erythrocytes, fluctuations in the P50 with an amplitude of 2-5 mmHg were measured at +37 degrees C; these fluctuations depend on the storage age of the erythrocytes and the glucose content of the incubation medium. Fenoterol has no effect on the amplitude, nor on the frequency of this P50 fluctuation. The glycolytic activity of the erythrocytes, relative to the 2,3-DPG and ATP content, also remains uninfluenced under Fenoterol. The addition of progesterone or cortisone to the incubation medium has no influence on the P50 of the maternal erythrocytes. In-vivo studies of the blood of pregnant women indicate changes of the P50 with maximal "shift to the left" after 6 hours and compensatory "shift to the right" after 20 hours under tokolysis. No fluctuations of the pH value were observed in our patients. The intraerythrocytic 2,3-DPG concentration changes simultaneously with the P50. Venous pO2 increases by approx. 12 mmHg in the first 3 hours following the start of tokolysis. However, the changes in the venous pO2 are not simultaneous with the changes in the P50. It can be stated that the progesterone level has no influence on the release of O2 from the maternal blood.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolism of thymoxamine. I. Studies with 14C-thymoxamine in rats.

Thymoxamine is rapidly and completely absorbed in rats. It is a prodrug which does not enter the systemic circulation in its unchanged form. After either oral or intravenous administration it undergoes rapid and intense metabolism involving four biotransformation reactions: Enzymatic hydrolysis to the corresponding phenol (metabolite I), Monodemethylation to metabolite II, Sulfate conjugation of I and II (metabolites III and IV) and Conjugation of I and II with glucuronic acid (metabolites V and VI). With these 6 metabolites identified approximately 95% of the radioactivity can be accounted for in plasma, urine and bile. Whereas the systemic availability of I and II is low, III and IV show high bioavailability. Metabolites I to IV are pharmacologically active, while III and IV are less potent than I and II. The radioactivity distribution in tissues is different after oral and intravenous administration consistent with the higher portion of unconjugated metabolites in the body after administration by parenteral route. Although 60% of the labelled compounds is eliminated via bile, the radioactive compounds are almost completely excreted in the urine after both routes of administration. This demonstrates complete reabsorption of the biliary metabolites. Secondary peaks of radioactivity in plasma and organs at 4 hours are explained by the participation of the metabolites in the enterohepatic circulation.

[Doppler studies of arterial blood flow in the uterus during labor]. / Doppleruntersuchungen des arteriellen uterinen Flows während der Wehentätigkeit.

By the pulsed doppler method the arterial uterine blood velocity was studied in 19 patients with contractions before and during labour. It is shown, that uterine contractions reduce blood velocity significantly. Normally there is a low resistance in uterine arteries, so that the diastolic flow is nearly as high as the systolic flow. In uterine contractions the vascular resistance increases. Systolic flow is reduced slightly and diastolic flow severely or completely. But a complete zero-flow couldn't observed in any studied uterine contraction.

[Late results in fallopian tubes studies on the Bleier clip]. / Spätergebnisse bei der Tubenuntersuchung mit dem Bleier-Clip.

We report on 243 patients with sterilisation by the Bleier Clip. 234 patients were operated by coeliotomia posterior. 9 cases were sterilized in combination with Caesarean section. In 4 of 243 women we observed pregnancies during the follow-up period (failure rate = 16%). The mean time of the 4 conceptions after operation was 43 months. This result shows that the primary cause was not the operation technique but the systemic failure of the Bleier Clip. In cases with controls by hysterosalpingography all Fallopian tubes were occluded, 84% together with a sactosalpinx.

[Intrauterine fetal movements and their significance for the condition of the fetus]. / Intrauterine Kindsbewegungen und ihre Aussage über den Zustand des Feten.

A literature review reports the results of investigations about fetal intrauterine activity. Different methods of observation are demonstrated and discussed. The results indicate that real-time-ultrasound is an accurate method for observation of fetal movements. Different patterns are identified: 1. Fetal body and extremity movements Development of fetal activity in early pregnancy is looked at as a process of maturation associated with fetal cerebral function. After 12 weeks of pregnancy typical patterns are established and seen also in the following weeks. Different results are reported about frequency of fetal movements related to duration of pregnancy. A circadian rhythm seems to be associated with a peak in activity between 2100 and 0100 hours, although fetal activity is altered by a variety of drugs and external stimuli. The proportion of pathological foetal movements in early pregnancy seems higher in patients who aborted. There are findings in later pregnancy, which report good fetal outcome, if daily fetal movement recording is greater than 10 movements for 12 hours. 2. Fetal breathing movements are recognized as being normally present, but episodic, shallow and variable in rate and regularity. There is a great variability in the percentage of time fetuses spend making breathing movements (mean 30-50% per hour; range 0-80%). Under physiological conditions there is a circadian rhythm concomitant with changes in fetal low-voltage electrocortical activity. The activation of fetal breathing occurs mainly during rapid-eye-movement-sleep, but the physiologic control of the activation has not been identified. Apnea, frequency, variability and amplitude of breathing, continuous breathing or gasping are described, but positive identification of abnormal pattern is not achieved. Several factors affecting fetal breathing movements have been described, their physiologic significance and control and their clinical relevance remain to be clearly elucidated. 3. Total fetal activity Fetal biophysical variables such as tone, breathing, body and extremity movements and heart rate reactivity are initiated and regulated by the fetal central nervous system, and as such, the presence of a given variable is indirect evidence of a functioning and intact central nervous system. These variable could be depressed by hypoxemia or other factors. Data in literature suggest that combined fetal biophysical testing is a more accurate method of antepartum fetal evaluation than any single method.

[Enzymatic lecithin determination in amniotic fluid for antepartal diagnosis of lung maturity - a multi-center study (author's transl)]. / Enzymatishce Lezithinbestimmung in fruchtwasser zur antepartalen Lungenreifediagnostik - Eine multizentrische Studie.

A new test-combination for the enzymatic determination of lecithin in amniotic fluid for the assessment of fetal lung maturity has been developed by Boehringer Mannheim. This test was evaluated by 12 hospitals and has been compared with the L/S ratio, the foam-test or the densitometric determination of lecithin. The assay is based on the hydrolysis of lecithin by phospholipase C which starts an enzymatic chain reaction in which NADH consumption if measured photometrically. The intra- and interassay precision were characterized by CV values below 10%. Average recoveries of lecithin were 95-102%. It is recommended to centrifuge the samples (10 min, 700 g) and to start the analysis as soon as possible after receipt of the specimen. The total amount of time required is 2 hours for a single determination. Batches of up to 10 samples require little extra time. An opened test-combination can be used for a maximum of 30 single determinations. Comparison of the quantitative enzymatic lecithin determination with other methods showed that the critical value for lecithin is 5.0 mg/100 ml. Above 5.1 mg/100 ml no case respiratory distress syndrome was observed. The good precision accuracy and the simple handling make the enzymatic lecithin determination suitable for routine use.

[Ultrastructural aspects of amniotic-fluid cells B. "vital cells" (author's transl)]. / Zur Feinmorphologie der Fruchtwasserzellen. B. "Vitale Zellen".

It has been shown, that apart from the mass of non-vital squamous epithelial cells, there also exist vital cells in the amniotic fluid. In this study, two types of amniotic fluid cells, which upon examination based on morphological characteristics gave rise to conclusions concerning their vitality, are presented, described and correlated with morphologically similar cells with known origin. Probably one type of these amniotic fluid cells are macrophages or Hofbauer-cells and the other types could be amnion-cells.

["Ultrastructural aspects of amniotic-fluid cells" A. non-vital cells. iii. large squamous cells (author's transl)]. / "Zur Feinmorphologie der Fruchtwasserzellen" A. Nichtvitale Zellen. Teil III: Grosse Plattenepithelien.

Until desquamation of vernix caseosa near the end of gestation the large, non-keratinizing squamous cells, which have their origin mostly from upper intestinal tract, vagina and urinary tract, form the majority of the population of cells in amniotic fluid. Their structure, as seen by electron microscopy is described, especially it's changes during the process of degeneration after the cell has been desquamated into amniotic fluid: dissolution or condensation of the nucleus, cytoplasmatic changes with appearance of filaments and vesicular corpuscles, and decreasing glycogen content.

["Ultrastructural aspects of amniotic-Fluid Cells". A. Non-vital cells. II. Keratinocytes (author's transl)]. / "Zur Feinmorphologie der Fruchtwasserzellen". A. nichtvitale Zellen. Teil II: Keratinozyten.

The ultrastructural morphology of epidermal keratinocytes, which at the end of pregnancy and after shedding of vernix represent the majority of amniotic fluid cell population, is analysed by electron microscopy. Special attention is focused on the morphological characteristics of epidermal keratinization according the changes of the cell's ultrastructure during this process: The transformation of the cytoplasma into keratin, the formation of the typical cell membrane of the keratinized squamous cells, and the findings concerning the intercellular space, especially of the zones of intercellular contact - desmosomes - and their changes.

["Ultrastructural aspects of amniotic-fluid cells". A. Non-vital cells. I. Periderm-cells (author's transl)]. / "Zur Feinmorphologie der Fruchtwasserzellen". A. nichtvitale Zellen. Teil 1: Periderm-Zellen.

The surface layer of fetal epidermis in early pregnancy, the Periderm, is progressingly replaced by the final keratinization process during fifth to sixth month of gestation. Then the peridermal cells are shed into the amniotic fluid. It is still controversial, whether complete peridermal cells or just their globular protrusions are separated. Formation of mikrovilli and invaginations of plasma membrane, the numerous smaller and larger vacuoles and the cytoplasmatic meshwork of fine filaments without production of keratohyaline, are characteristics of peridermal cells, and are described in detail by electron microscopical investigations on cells suspended in the amniotic fluid, which are most likely of peridermal origin.

[The oxycardiotocogram (OCTG). A new possibility of time-synchronous recording (author's transl)]. / Das Oxykardiotokogramm (OCTG) -- Eine neue Möglichkeit zur zeitsynchronen Registrierung.

A new recording instrument for intrapartal parameters (fetal heart rate, uterine pressure, fetal transcutaneous oxygen pressure, local perfusion) records waveforms familiar to the obstetrician. The form of the recording corresponds to experience gained from cardiotocogram. The additional waveforms, oxygen pressure and perfusion are recorded synchronously in the recording channels of the other waveforms and are differentiated by special traces. This supplementary information given by the current oxygen-pressure waveforms can be comprehended synoptically. These parameter changes in respect to the fetal heart rate and uterine pressure can be identified clearly at a glance. Thus, the obstetrician is offered a recording of the monitored intrapartal parameters in waveforms which are familiar and extensively interpretable.