Re-evaluation of HER2 status in metastatic breast cancer and tumor-marker guided therapy with vinorelbine and trastuzumab

Background: HER2 is overexpressed in 20 - 30% of breast cancers. Compared to chemotherapy alone, chemotherapy with trastuzumab improves clinical outcome in patients with HER2- positive metastatic breast cancer ( MBC). In general, HER2 status in a primary lesion predicts the status of metastases, so that biopsy of metastatic lesions appears unnecessary. Case Report: A 39- year old woman was diagnosed with primary breast cancer in November 2000. Using the method and scoring system of the DAKO Hercep Test, the tumor has shown low HER2 expression ( DAKO score 1+). After failure of several chemotherapy regimens for metastatic disease ( liver, skeletal), the patient underwent CT- guided needle biopsy of the liver which showed HER2 positive adenocarcinoma ( DAKO score 3+). In consequence, the patient was treated with vinorelbine ( 30 mg/ m(2) d1,8,15 q4w) and trastuzumab ( 4 mg/ kg loading dose, 2 mg/ kg weekly). During a treatment period of 4 months imaging results as well as tumor marker kinetics indicated an excellent response with sustained decrease of tumor markers. A retrospective analysis of the HER2 shed antigen in metastatic stage revealed excessively increased serum levels and supports HER2 overexpression observed in liver metastasis. The kinetics of the HER2 shed antigen during therapy for metastatic disease were found to be in phase with the kinetics of CEA and CA15- 3. Conclusion: This case report demonstrates that re- evaluation of the HER2 status may be helpful in single patients not sufficiently responding to treatment of metastatic disease. Determination of HER2 overexpression may be facilitated by a determination of the HER2 shed antigen level in peripheral blood

Optimal Population Codes for Space: Grid Cells Outperform Place Cells

Rodents use two distinct neuronal coordinate systems to estimate their position: place fields in the hippocampus and grid fields in the entorhinal cortex. Whereas place cells spike at only one particular spatial location, grid cells fire at multiple sites that correspond to the points of an imaginary hexagonal lattice. We study how to best construct place and grid codes, taking the probabilistic nature of neural spiking into account. Which spatial encoding properties of individual neurons confer the highest resolution when decoding the animal’s position from the neuronal population response? A priori, estimating a spatial position from a grid code could be ambiguous, as regular periodic lattices possess translational symmetry. The solution to this problem requires lattices for grid cells with different spacings; the spatial resolution crucially depends on choosing the right ratios of these spacings across the population. We compute the expected error in estimating the position in both the asymptotic limit, using Fisher information, and for low spike counts, using maximum likelihood estimation. Achieving high spatial resolution and covering a large range of space in a grid code leads to a trade-off: the best grid code for spatial resolution is built of nested modules with different spatial periods, one inside the other, whereas maximizing the spatial range requires distinct spatial periods that are pairwisely incommensurate. Optimizing the spatial resolution predicts two grid cell properties that have been experimentally observed. First, short lattice spacings should outnumber long lattice spacings. Second, the grid code should be self-similar across different lattice spacings, so that the grid field always covers a fixed fraction of the lattice period. If these conditions are satisfied and the spatial “tuning curves” for each neuron span the same range of firing rates, then the resolution of the grid code easily exceeds that of the best possible place code with the same number of neurons

Gemcitabine and carboplatin in intensively pretreated patients with metastatic breast cancer

Background: Patients with metastatic breast cancer (MBC) are increasingly exposed to anthracyclines and taxanes either during treatment of primary breast cancer or during initial therapy of metastatic disease. The combination of gemcitabine and carboplatin was therefore investigated as an anthracycline- and taxane-free treatment option. Patients and Methods: MBC patients previously treated with chemotherapy were enrolled in a multicenter phase II study. Treatment consisted of gemcitabine (1,000 mg/m(2) i.v. on days 1 and 8) and carboplatin (AUC 4 i.v. on day 1) applied every 3 weeks. Results: Thirty-nine patients were recruited, and a total of 207 treatment cycles were applied with a median of 5 cycles per patient. One complete response and 11 partial responses were observed for an overall response rate of 31% (95% CI: 17-48%). Twelve patients (31%) had stable disease. Median time to progression was 5.3 months (95% CI: 2.6-6.7 months) and median overall survival from start of treatment was 13.2 months (95% CI: 8.7-16.7 months). Grade 3/4 hematological toxicity included leukopenia (59%/5%), thrombo-cytopenia (26%/23%) and anemia (10%/0%). Nonhematological toxicity was rarely severe. Conclusion: Combination chemotherapy with gemcitabine and carboplatin is an effective and generally well-tolerated treatment option for intensively pretreated patients with MBC. Due to a considerable incidence of severe thrombocytopenia it would be reasonable to consider starting gemcitabine at the lower dose level of 800 mg/m(2). Copyright (c) 2008 S. Karger AG, Basel

Light absorption by marine cyanobacteria affects tropical climate mean state and variability

Observations indicate that positively buoyant marine cyanobacteria, which are abundant throughout the tropical and subtropical ocean, have a strong local heating effect due to light absorption at the ocean surface. How these local changes in radiative heating affect the climate system on the large scale is unclear. We use the Max Planck Institute Earth System Model (MPI-ESM), include light absorption by cyanobacteria, and find a considerable cooling effect on tropical sea surface temperature (SST) in the order of 0.5&thinsp;K on a climatological timescale. This cooling is caused by local shading of subtropical subsurface water by cyanobacteria that is upwelled at the Equator and in eastern boundary upwelling systems. Implications for the climate system include a westward shift of the Walker circulation and a weakening of the Hadley circulation. The amplitude of the seasonal cycle of SST is increased in large parts of the tropical ocean by up to 25&thinsp;%, and the tropical Pacific interannual variability is enhanced by approx. 20&thinsp;%. This study emphasizes the sensitivity of the tropical climate system to light absorption by cyanobacteria due to its regulative effect on tropical SST. Generally, including phytoplankton-dependent light attenuation instead of a globally uniform attenuation depth improves some of the major model temperature biases, indicating the relevance of taking this biophysical feedback into account in climate models.</p

Markov analysis of stochastic resonance in a periodically driven integrate-fire neuron

We model the dynamics of the leaky integrate-fire neuron under periodic stimulation as a Markov process with respect to the stimulus phase. This avoids the unrealistic assumption of a stimulus reset after each spike made in earlier work and thus solves the long-standing reset problem. The neuron exhibits stochastic resonance, both with respect to input noise intensity and stimulus frequency. The latter resonance arises by matching the stimulus frequency to the refractory time of the neuron. The Markov approach can be generalized to other periodically driven stochastic processes containing a reset mechanism.Comment: 23 pages, 10 figure

A higher-resolution version of the Max Planck Institute Earth System Model (MPI-ESM1.2-HR)

The MPI‐ESM1.2 is the latest version of the Max Planck Institute Earth System Model and is the baseline for the Coupled Model Intercomparison Project Phase 6 and current seasonal and decadal climate predictions. This paper evaluates a coupled higher‐resolution version (MPI‐ESM1.2‐HR) in comparison with its lower‐resolved version (MPI‐ESM1.2‐LR). We focus on basic oceanic and atmospheric mean states and selected modes of variability, the El Niño/Southern Oscillation and the North Atlantic Oscillation. The increase in atmospheric resolution in MPI‐ESM1.2‐HR reduces the biases of upper‐level zonal wind and atmospheric jet stream position in the northern extratropics. This results in a decrease of the storm track bias over the northern North Atlantic, for both winter and summer season. The blocking frequency over the European region is improved in summer, and North Atlantic Oscillation and related storm track variations improve in winter. Stable Atlantic meridional overturning circulations are found with magnitudes of ~16 Sv for MPI‐ESM1.2‐HR and ~20 Sv for MPI‐ESM1.2‐LR at 26°N. A strong sea surface temperature bias of ~5°C along with a too zonal North Atlantic current is present in both versions. The sea surface temperature bias in the eastern tropical Atlantic is reduced by ~1°C due to higher‐resolved orography in MPI‐ESM‐HR, and the region of the cold‐tongue bias is reduced in the tropical Pacific. MPI‐ESM1.2‐HR has a well‐balanced radiation budget and its climate sensitivity is explicitly tuned to 3 K. Although the obtained reductions in long‐standing biases are modest, the improvements in atmospheric dynamics make this model well suited for prediction and impact studies

Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients

In patients with human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer, treatment with trastuzumab has been shown to markedly improve the outcome. We investigated the role of trastuzumab on brain metastasis (BM) in HER2-positive breast cancer patients. From 1999 to 2006, 251 patients were treated with palliative chemotherapy for HER2-positive metastatic breast cancer at Samsung Medical Center. The medical records of these patients were analysed to study the effects of trastuzumab on BM prevalence and outcomes. Patients were grouped according to trastuzumab therapy: pre-T (no trastuzumab therapy) vs post-T (trastuzumab therapy). The development of BM between the two treatment groups was significantly different (37.8% for post-T vs 25.0% for pre-T, P=0.028). Patients who had received trastuzumab had longer times to BM compared with patients who were not treated with trastuzumab (median 15 months for post-T group vs 10 months for pre-T group, P=0.035). Time to death (TTD) from BM was significantly longer in the post-T group than in the pre-T group (median 14.9 vs 4.0 months, P=0.0005). Extracranial disease control at the time of BM, 12 months or more of progression-free survival of extracranial disease and treatment with lapatinib were independent prognostic factors for TTD from BM

Switching Time Statistics for Driven Neuron Models: Analytic Expressions versus Numerics

Analytical expressions are put forward to investigate the forced spiking activity of abstract neuron models such as the driven leaky integrate-and-fire (LIF) model. The method is valid in a wide parameter regime beyond the restraining limits of weak driving (linear response) and/or weak noise. The novel approximation is based on a discrete state Markovian modeling of the full dynamics with time-dependent rates. The scheme yields very good agreement with numerical Langevin and Fokker-Planck simulations of the full non-stationary dynamics for both, the first-passage time statistics and the interspike interval (residence time) distributions.Comment: 4 pages, 4 figures, RevTeX4 used, final versio

Learning intrinsic excitability in medium spiny neurons

We present an unsupervised, local activation-dependent learning rule for intrinsic plasticity (IP) which affects the composition of ion channel conductances for single neurons in a use-dependent way. We use a single-compartment conductance-based model for medium spiny striatal neurons in order to show the effects of parametrization of individual ion channels on the neuronal activation function. We show that parameter changes within the physiological ranges are sufficient to create an ensemble of neurons with significantly different activation functions. We emphasize that the effects of intrinsic neuronal variability on spiking behavior require a distributed mode of synaptic input and can be eliminated by strongly correlated input. We show how variability and adaptivity in ion channel conductances can be utilized to store patterns without an additional contribution by synaptic plasticity (SP). The adaptation of the spike response may result in either "positive" or "negative" pattern learning. However, read-out of stored information depends on a distributed pattern of synaptic activity to let intrinsic variability determine spike response. We briefly discuss the implications of this conditional memory on learning and addiction.Comment: 20 pages, 8 figure

Children's trust and the development of prosocial behavior

This study examined the role of children’s trust beliefs and trustworthiness in the development of prosocial behavior using data from four waves of a longitudinal study in a large, ethnically diverse sample of children in Switzerland (mean age = 8.11 years at Time 1, N = 1,028). Prosocial behavior directed towards peers was measured at all assessment points by teacher reports. Children’s trust beliefs and their trustworthiness with peers were assessed and calculated by a social relations analysis at the first assessment point using children’s reports of the extent to which classmates kept promises. In addition, teacher reports of children’s trustworthiness were assessed at all four assessment points. Latent growth curve modeling yielded a decrease in prosocial behavior over time. Peer- and teacher-reported trustworthiness predicted higher initial levels of prosocial behavior, and peer-reported trustworthiness predicted less steep decreases in prosocial behavior over time. Autoregressive cross-lagged analysis also revealed bidirectional longitudinal associations between teacher-reported trustworthiness and prosocial behavior. We discuss the implications of the findings for research on the role of trust in the development of children’s prosocial behavior