Long-term survival of breast cancer patients with brain metastases: subanalysis of the BMBC registry.

BACKGROUND: Up to 30% of metastatic breast cancer (BC) patients develop brain metastases (BM). Prognosis of patients with BM is poor and long-term survival is rare. Identification of factors associated with long-term survival is important for improving treatment modalities. PATIENTS AND METHODS: A total of 2889 patients of the national registry for BM in BC (BMBC) were available for this analysis. Long-term survival was defined as overall survival (OS) in the upper third of the failure curve resulting in a cut-off of 15 months. A total of 887 patients were categorized as long-term survivors. RESULTS: Long-term survivors compared to other patients were younger at BC and BM diagnosis (median 48 versus 54 years and 53 versus 59 years), more often had HER2-positive tumors (59.1% versus 36.3%), less frequently luminal-like (29.1% versus 35.7%) or triple-negative breast cancer (TNBC) (11.9% versus 28.1%), showed better Eastern Cooperative Oncology Group (ECOG) performance status (PS) at the time of BM diagnosis (ECOG 0-1, 76.9% versus 51.0%), higher pathological complete remission rates after neoadjuvant chemotherapy (21.6% versus 13.7%) and lower number of BM (n = 1, BM 40.9% versus 25.4%; n = 2-3, BM 26.5% versus 26.7%; n ≥4, BM 32.6% versus 47.9%) (P < 0.001). Long-term survivors had leptomeningeal metastases (10.4% versus 17.5%) and extracranial metastases (ECM, 73.6% versus 82.5%) less frequently, and asymptomatic BM more often at the time of BM diagnosis (26.5% versus 20.1%), (P < 0.001). Median OS in long-term survivors was about two times higher than the cut-off of 15 months: 30.9 months [interquartile range (IQR) 30.3] overall, 33.9 months (IQR 37.1) in HER2-positive, 26.9 months (IQR 22.0) in luminal-like and 26.5 months (IQR 18.2) in TNBC patients. CONCLUSIONS: In our analysis, long-term survival of BC patients with BM was associated with better ECOG PS, younger age, HER2-positive subtype, lower number of BM and less extended visceral metastases. Patients with these clinical features might be more eligible for extended local brain and systemic treatment.

Characteristics of patients with brain metastases from human epidermal growth factor receptor 2-positive breast cancer: subanalysis of Brain Metastases in Breast Cancer Registry.

BACKGROUND: Up to 40% of patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer develop brain metastases (BMs). Understanding of clinical features of these patients with HER2-positive breast cancer and BMs is vital. PATIENTS AND METHODS: A total of 2948 patients from the Brain Metastases in Breast Cancer registry were available for this analysis, of whom 1311 had primary tumors with the HER2-positive subtype. RESULTS: Patients with HER2-positive breast cancer and BMs were-when compared with HER2-negative patients-slightly younger at the time of breast cancer and BM diagnosis, had a higher pathologic complete response rate after neoadjuvant chemotherapy and a higher tumor grade. Furthermore, extracranial metastases at the time of BM diagnosis were less common in HER2-positive patients, when compared with HER2-negative patients. HER2-positive patients had more often BMs in the posterior fossa, but less commonly leptomeningeal metastases. The median overall survival (OS) in all HER2-positive patients was 13.2 months (95% confidence interval 11.4-14.4). The following factors were associated with shorter OS (multivariate analysis): older age at BM diagnosis [≥60 versus <60 years: hazard ratio (HR) 1.63, P < 0.001], lower Eastern Cooperative Oncology Group status (2-4 versus 0-1: HR 1.59, P < 0.001), higher number of BMs (2-3 versus 1: HR 1.30, P = 0.082; ≥4 versus 1: HR 1.51, P = 0.004; global P = 0.015), BMs in the fossa anterior (HR 1.71, P < 0.001), leptomeningeal metastases (HR 1.63, P = 0.012), symptomatic BMs at diagnosis (HR 1.35, P = 0.033) and extracranial metastases at diagnosis of BMs (HR 1.43, P = 0.020). The application of targeted therapy after the BM diagnosis (HR 0.62, P < 0.001) was associated with longer OS. HER2-positive/hormone receptor-positive patients showed longer OS than HER2-positive/hormone receptor-negative patients (median 14.3 versus 10.9 months; HR 0.86, P = 0.03), but no differences in progression-free survival were seen between both groups. CONCLUSIONS: We identified factors associated with the prognosis of HER2-positive patients with BMs. Further research is needed to understand the factors determining the longer survival of HER2-positive/hormone receptor-positive patients.

Treatment and outcomes of patients in the Brain Metastases in Breast Cancer Network Registry.

BACKGROUND: Brain metastases (BMs) have a major impact on life expectancy and quality of life for many breast cancer patients. Knowledge about treatment patterns and outcomes is limited. METHODS: We analysed clinical data of 1712 patients diagnosed with BMs from breast cancer between January 2000 and December 2016 at 80 institutions. RESULTS: Median age at diagnosis of BMs was 56 years (22-90 years). About 47.8% (n = 732) of patients had HER2-positive, 21.4% (n = 328) had triple-negative and 30.8% (n = 471) had hormone receptor (HR)-positive, HER2-negative (luminal-like) primary tumours. The proportion of patients with HER2-positive BMs decreased comparing the years 2000-2009 with 2010-2015 (51%-44%), whereas the percentage of patients with luminal-like tumours increased (28%-34%; p = 0.0331). Patients with BMs in the posterior fossa were more often HER2 positive (n = 169/314, 53.8%) than those diagnosed with triple-negative (n = 65/314, 20.7%) or luminal-like primary breast cancer (n = 80/314, 25.5%), (p < 0.0001). Median overall survival (OS) time after development of BMs for the overall cohort was 7.4 months (95% confidence interval [CI]: 6.7-8.0 months). One-year survival rate was 37.7% (95% CI: 35.2-40.1). Patients with HER2-positive tumours had the longest median OS of 11.6 months (95% CI: 10.0-13.4) compared with 5.9 months (95% CI: 5.0-7.2) for patients with luminal-like and 4.6 months (95% CI: 3.9-5.4) for patients with triple-negative tumours. Patients with HER2-positive tumours who received anti-HER2 treatment had longer median OS than those without (17.1 months versus 7.2 months, p < 0.0001). CONCLUSIONS: Prognosis of patients after developing BMs varies significantly according to the subtype. The outcome in this cohort is similarly poor in triple-negative and HR-positive/HER2-negative patients. Our results underline the high medical need for improvement of treatment and prevention strategies for BMs in breast cancer patients.

Cognitive interventions in mild Alzheimer's disease: a therapy-evaluation study on the interaction of medication and cognitive treatment.

BACKGROUND/AIMS: Many studies have shown that not only pharmacological treatment but also cognitive stimulation in the early stages of Alzheimer's disease (AD) improves language processing and (other) cognitive functions, stabilizes Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) functions and increases the subjective quality of life (wherein a combination of pharmacological intervention and cognitive stimulation could provide greater relief of clinical symptoms than either intervention given alone). Today, it is no longer the question of whether cognitive stimulation helps but rather what kind of stimulation helps more than others. METHODS: A sample of 42 subjects with mild AD (all medicated with an acetylcholinesterase inhibitor and well adjusted) underwent clinical and cognitive evaluation and participated in a 6-month study with 2 experimental groups (i.e. 'client-centered' global stimulation vs. cognitive training) and a control group. Since the test performance also depends on the individual test, we used a wide variety of tests; we z-transformed the results and then calculated the mean value for the global cognitive status (using the Mini-Mental State Examination) as well as for the single functional areas. RESULTS: Between-group differences were found, they were overall in favor of the experimental groups. Different functional areas led to different treatment and test patterns. Client-centered, global, cognitive therapy stimulated many cognitive functions and thus led to a better performance in language processing and ADL/IADL. The subjective quality of life increased as well. The cognitive training (of working memory) improved only the ADL/IADL performance (more, however, than client-centered, global, cognitive stimulation) and stabilized the level of performance in the other three functional areas. © 2013 S. Karger AG, Basel.

Wastewater recycling concept for an urban multi-storey building.

An innovative system for blackwater recycling is described. An existing building comprising of 32 flats built in 1962 was renovated and equipped with vacuum toilets to collect blackwater separately. The energy and water consumption was determined. The flushing water consumption decreased from 40 l/p/d to 9 l/p/d.

Weekly intravenous recombinant humanized anti-P185HER2 monoclonal antibody (herceptin) plus docetaxel in patients with metastatic breast cancer: a pilot study.

BACKGROUND: In patients with HER2-positive metastatic breast cancer (MBC), combined treatment of herceptin (H) and chemotherapy (CT) improves time to progression, response rates and survival compared with CT alone. MATERIALS AND METHODS: We evaluated the safety and efficacy of weekly Docetaxel combined with weekly H as treatment in HER2 overexpressing MBC. RESULTS: Preliminary toxicity data from 12 patients and 76 cycles of D and 80 cycles of H were analysed. No G3/4 toxicity was observed. The most frequent non-hematologic toxicities were fatigue (2 patients G2, 2 patients G1), dyspepsia (1 patients G2, 3 patients G1), diarrhea (1 patient G2, 3 patients G1), and nausea (1 patient G2, 3 patients G1). Six partial responses have been observed in 12 patients (ORR 50%). CONCLUSIONS: The combination of weekly Docetaxel and Herceptin is well tolerated with significant anti-tumor activity.

First experimental test of a trace formula for billiard systems showing mixed dynamics.

In general, trace formulas relate the density of states for a given quantum mechanical system to the properties of the periodic orbits of its classical counterpart. Here we report for the first time on a semiclassical description of microwave spectra taken from superconducting billiards of the Limaçon family showing mixed dynamics in terms of a generalized trace formula derived by Ullmo et al. [Phys. Rev. E 54, 136 (1996)]. This expression not only describes mixed-typed behavior but also the limiting cases of fully regular and fully chaotic systems and thus presents a continuous interpolation between the Berry-Tabor and Gutzwiller formulas.

Enhancement characteristics of liver metastases, hepatocellular carcinomas, and hemangiomas with Gd-EOB-DTPA: preliminary results with dynamic MR imaging.

Our objective was to study Gd-EOB-DTPA for the characterization of focal liver lesions by means of dynamic MR imaging. A double-blind and randomized dose-ranging phase-2 clinical trial was performed in 31 patients (liver metastases n = 23, hepatocellular carcinoma n = 4, and hemangioma n = 4) at a field strength of 1.0 Tesla. Gd-EOB-DTPA (Schering AG, Berlin, Germany) was administered as an IV bolus (12.5, 25, or 50 micromol/kg body weight) with dynamic T1-weighted MRI during the distribution and cellular uptake of the contrast agent at multiple time points up to 45 min post contrast. Dynamic changes in tumor signal intensity, tumor-liver contrast, enhancement patterns, side effects, and adverse events were evaluated. Monitoring of vital signs revealed no significant changes during bolus injection of Gd-EOB-DTPA. Liver metastases demonstrated an inhomogeneous uptake of Gd-EOB-DTPA during the distribution phase with a washout effect on delayed images > 3 min and highest tumor-liver contrast 20 and 45 min post contrast. Hepatocellular carcinomas showed prolonged enhancement as compared with metastases and hemangiomas. Hemangiomas exhibited an early peripheral-nodular enhancement with subsequent partial or complete filling, persisting enhancement < 10 min following injection of Gd-EOB-DTPA, and delayed washout as compared with liver metastases. Initial clinical experience suggests that Gd-EOB-DTPA as a bolus injectable hepatobiliary MR contrast agent may offer useful features for the characterization of focal liver lesions.

Phase II clinical evaluation of Gd-EOB-DTPA: dose, safety aspects, and pulse sequence.

PURPOSE: To investigate the efficacy of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) in the detection of focal liver lesions with respect to dose, side effects, and pulse sequence. MATERIALS AND METHODS: A randomized double-blinded trial was performed in 33 patients with focal solid liver lesions. A bolus of Gd-EOB-DTPA, a liver-specific contrast agent, was intravenously administered at three different doses (12.5, 25, and 50 mumol per kilogram of body weight). Magnetic resonance imaging with different T1-weighted techniques was performed 20 and 45 minutes after administration of Gd-EOB-DTPA. Changes in liver signal intensity, lesion-liver contrast-to-noise ration (C/N), detectable liver lesions, side effects, and adverse events were evaluated. RESULTS: Gd-EOB-DTPA significantly (P < .05) increased liver signal intensity and lesion-liver C/N within the dose range tested. Lesion detection was improved 20 and 45 minutes after administration of Gd-EOB-DTPA. A dose of 12.5 mumol was sufficient for the detection of focal liver lesions, and the breath-hold, T1-weighted, fast low-angle shot pulse sequence was the most useful. No significant changes in vital signs, clinical laboratory test results, and urinalysis were observed. CONCLUSION: Gd-EOB-DTPA is an efficient, diagnostically useful, and safe contrast agent.

[New MR contrast media in liver diagnosis. Initial clinical results with hepatobiliary Eovist (gadolinium-EOB-DTPA) and RES-specific Resovist (SH U 555 A)]. / Neue MR-Kontrastmittel in der Leberdiagnostik. Erste klinische Ergebnisse mit hepatobilliärem Eovist (Gadolinium-EOB-DTPA) und RES-spezifischem Resovist (SH U 555 A).

The purpose of this work is to describe our initial clinical experience (in 66 patients) with Resovist and Eovist, two new liver-specific MR contrast agents. We focus our report on safety aspects, dose finding, and optimization and technical parameters. Both contrast agents were well tolerated and improved the detectability of focal liver lesions. With Resovist, postcontrast MRI may be started as early as 10 min following injection. The dose of 8 mumol Fe/kg bodyweight was sufficient to achieve diagnostic tumor-liver contrast levels. Since Eovist can also be administered as a bolus, dynamic enhancement patterns may be studied for tumor characterization as well. Breath-hold T1-weighted FLASH images were superior to other T1-weighted techniques with and without fat saturation.

[Spinal para-medullary conduction anesthesia in therapy with anticoagulant drugs]. / Rückenmarknahe Leitungsanästhesie bei Therapie mit gerinnungshemmenden Medikamenten.

Epidural and spinal blocks can lead to iatrogenic bleeding in the spinal canal. Incidence of this severe complication is considered low, but the risk of irreversible neurological defects for the patient requires increased attention by the anaesthetist. The perioperative risk is higher in patients under anticoagulant therapy. The different pharmacodynamics and pharmacokinetics of practically relevant anticoagulants are discussed and recommendations for the performance of centroneuraxis blocks in patients under anticoagulant therapy are given.

Two members of the ERabp gene family are expressed differentially in reproductive organs but to similar levels in the coleoptile of maize.

A Zea mays cDNA clone, ZmERabp4, coding for a new member of the auxin-binding protein family was isolated. The primary amino acid sequence contains an N-terminal hydrophobic leader sequence, a potential glycosylation site (Asn136-Thr-Thr) and a C-terminal KDEL motif known to be responsible for retention of proteins within the lumen of the ER. The expression pattern of the ZmERabp4 gene in various organs of maize differs from the expression pattern previously observed for the ZmERabp1 gene. The ZmERabp4 gene is expressed highly in male flower organs, whereas the ZmERabp1 gene shows highest expression in female flower parts. In situ hybridization and analysis by laser scanning microscopy revealed enhanced levels of expression for both genes in the coleoptile when compared with the primary leaf of etiolated maize seedlings.

Molecular analysis of three maize 22 kDa auxin-binding protein genes--transient promoter expression and regulatory regions.

The site I 22 kDa auxin-binding proteins from maize are encoded by a small gene family comprising at least five members. Here the cloning and molecular analysis of the Zm-ERabp1, Zm-ERabp4, and Zm-ERabp5 genes is presented. All three encode 22-23 kDa proteins displaying a transit peptide, a C-terminal KDEL sequence, as well as glycosylation and auxin-binding sites. The Zm-ERabp4 and Zm-ERabp5 genes are very similar. The Zm-ERabp1 gene encodes a related protein, but its promoter, leader and signal peptide are very different. Northern analysis using gene-specific oligonucleotide probes indicates that Zm-ERabp4 is expressed in leaves and coleoptiles but weakly in roots, whereas Zm-ERabp5 expression is barely detectable in these tissues. RNA-PCR indicated that all three genes are none the less expressed in many tissues. Primer-extension analysis revealed an unusually long (320 bases) Zm-ERabp1 leader containing an 80 codon ORF which, if expressed, would encode a positively charged protein with some similarity to transcription factors. In a transient promoter-reporter gene expression system using maize leaf protoplasts the Zm-ERabp1 promoter is more active than the Zm-ERabp4 and Zm-ERabp5 promoters. Promoter deletion analysis of Zm-ERabp1 has identified a negative regulatory sequence in a region from -364 bp and -130 bp, deletion of which results in about twofold higher expression. This region contains both enhancer- and G-box-related sequences. Deletion of -126 bp to +64 bp, which contains the TATA box and transcription start, results in a large decrease in expression.

Molecular analysis of an auxin binding protein gene located on chromosome 4 of Arabidopsis.

We have isolated a cDNA clone from Arabidopsis, At-ERabp1, for the Arabidopsis auxin binding protein located in the lumen of the endoplasmic reticulum (ER). This cDNA clone codes for a protein related to the major auxin binding protein from maize, Zm-ERabp1. A single open reading frame, 594 bases in length, predicts a protein of 198 amino acid residues and a molecular mass of 22,044 D. The primary amino acid sequence contains an N-terminal hydrophobic signal sequence of 33 amino acids. We demonstrated by in vitro studies that the At-ERabp1 protein is translocated into ER-derived microsomes. The protein was processed, and the cleavage site for the N-terminal signal peptide was determined by radiosequencing. The mature protein is composed of 165 amino acid residues, with a molecular mass of 18,641 D. The At-ERabp1 protein contains potential N-glycosylation sites (Asn46-Ile-Ser and Asn130-Ser-Thr). In vitro transport studies demonstrated cotranslational glycosylation. Retention within the lumen of the ER correlates with an additional signal located at the C terminus and represented by the amino acids Lys196-Asp-Glu-Leu, well known to be essential for active retrieval of proteins into the lumen of the ER. DNA gel blot analysis of genomic DNA revealed single hybridizing bands, suggesting that only a single At-ERabp1 gene is present in the Arabidopsis genome. Restriction fragment length polymorphism mapping indeed revealed a single locus mapping to chromosome 4.

Hormonal modulation of plant growth: the role of auxin perception.

The organisation of growth and development in vascular plants appears to be highly adapted to meet the specific demands of a sessile, autotrophic habit. Many of the characteristic features of plant development are associated with the activities of five groups of phytohormones. Each of the phytohormones has the ability to influence fundamentally a remarkable variety of developmental and physiological processes. This ability has been widely documented but remains to be explained. Here we describe how recent breakthroughs in the analysis and understanding of eucaryotic signal transduction are being applied, in conjunction with technical advances in molecular genetics, to elucidate the molecular basis of the phytohormonal properties of auxin. Both auxin concentration, and the sensitivity of plant cells to this phytohormone have been implicated as important parameters in auxin action. We describe recent molecular biological approaches to assess the contribution made by each of these parameters. Emphasis is given to a description of recent genetic and biochemical progress towards identification of the molecular targets of the auxin signal and the molecular components involved in its subsequent transduction.

Auxin binding proteins from maize coleoptiles: purification and molecular characterization.

To understand precisely the mechanisms by which hormones like auxins regulate plant differentiation and development, it is essential to isolate putative hormone receptors. We have purified the major auxin binding protein from maize coleoptiles to homogeneity. The protein has an apparent molecular weight of 22,000 Da and binds 1-naphthylacetic acid with a KD of 2.4 x 10(-7) M. Protein sequence analysis allowed the construction of oligonucleotide probes to isolate a corresponding cDNA coding for this protein. The open reading frame of this cDNA predicts a protein of 201 amino acids and 21,990 Da in size. The amino acid sequence includes a cleavable N-terminal signal sequence and a C-terminal signal element consisting of the amino acids Lys Asp Glu Leu known to be responsible for preventing secretion of proteins from the lumen of the endoplasmic reticulum.