Implementing post-normal science with or for EU policy actors: using quantitative story-telling.

There is increasing recognition of the wicked nature of the intertwined climate, biodiversity and economic crises, and the need for adaptive, multi-scale approaches to understanding the complexity of both the problems and potential responses. Most science underpinning policy responses to sustainability issues, however, remains overtly apolitical and focussed on technical innovation; at odds with a critical body of literatures insisting on the recognition of systemic problem framing when supporting policy processes. This paper documents the experience of implementing a mixed method approach called quantitative story-telling (QST) to policy analysis that explicitly recognises this normative dimension, as the methodology is part of a post-normal science (PNS) toolkit. The authors reflect on what was learnt when considering how QST fared as a tool for science-policy interaction, working with European Union (EU) level policy actors interested in sustainable agriculture and sustainable development goal 2. These goals-also known as UN Agenda 2030-are the latest institutionalisation of the pursuit of sustainable development and the EU has positioned itself as taking a lead in its implementation. Thus, the paper illustrates our experience of using PNS as an approach to science policy interfaces in a strategic policy context; and illustrates how the challenges identified in the science-policy literature are amplified when working across multiple policy domains and taking a complex systems approach. Our discussion on lessons learnt may be of interest to researchers seeking to work with policy-makers on complex sustainability issues.

Impact of thoracic radiotherapy timing in limited-stage small-cell lung cancer: usefulness of the individual patient data meta-analysis.

BACKGROUND: Chemotherapy (CT) combined with radiotherapy is the standard treatment of 'limited-stage' small-cell lung cancer. However, controversy persists over the optimal timing of thoracic radiotherapy and CT. MATERIALS AND METHODS: We carried out a meta-analysis of individual patient data in randomized trials comparing earlier versus later radiotherapy, or shorter versus longer radiotherapy duration, as defined in each trial. We combined the results from trials using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival. RESULTS: Twelve trials with 2668 patients were eligible. Data from nine trials comprising 2305 patients were available for analysis. The median follow-up was 10 years. When all trials were analysed together, 'earlier or shorter' versus 'later or longer' thoracic radiotherapy did not affect overall survival. However, the HR for overall survival was significantly in favour of 'earlier or shorter' radiotherapy among trials with a similar proportion of patients who were compliant with CT (defined as having received 100% or more of the planned CT cycles) in both arms (HR 0.79, 95% CI 0.69-0.91), and in favour of 'later or longer' radiotherapy among trials with different rates of CT compliance (HR 1.19, 1.05-1.34, interaction test, P < 0.0001). The absolute gain between 'earlier or shorter' versus 'later or longer' thoracic radiotherapy in 5-year overall survival for similar and for different CT compliance trials was 7.7% (95% CI 2.6-12.8%) and -2.2% (-5.8% to 1.4%), respectively. However, 'earlier or shorter' thoracic radiotherapy was associated with a higher incidence of severe acute oesophagitis than 'later or longer' radiotherapy. CONCLUSION: 'Earlier or shorter' delivery of thoracic radiotherapy with planned CT significantly improves 5-year overall survival at the expense of more acute toxicity, especially oesophagitis.

Detection rate and outcome of colonic serrated epithelial changes in patients with ulcerative colitis or Crohn's colitis.

BACKGROUND: Chronic ulcerative colitis (CUC) and colonic Crohn's disease (CD) increase colorectal neoplasia (CRN) risk. While sessile serrated polyp (SSP) is a known cancer precursor, serrated epithelial changes (SEC) are of uncertain prevalence and neoplastic risk. AIM: To assess the serrated lesion detection rates in CUC and CD and documented incidence of subsequent CRN in a retrospective, single-centre cohort study. METHODS: Patients were identified by a central diagnostic index and pathology review confirmed SEC, SSP, CUC and CD diagnoses from 2006-12. Matched controls were identified from among all CUC and CD patients having colonoscopy during the second half of the time period. All were followed for incident CRN, estimated by the Kaplan-Meier method. RESULTS: Between 2006 and 2012, 79 SEC and 10 SSP cases were identified. Detection rates were estimated to be 10/1000 and 2/1000 patients, for SEC and SSP respectively, among 4208 unique CUC or CD patients having colonoscopy from 2010-12. With only 10 cases, SSP patients were not further analysed. Cumulative incidence of subsequent CRN at 1 and 3 years was 12% (95% CI, 0-30%) and 30% (3-57%), respectively, in SEC patients compared to 4% (0-12%) and 9% (0-23%), respectively, in CUC or CD controls (P = 0.047, log-rank). However, this statistical difference was not significant after patients were stratified for history of prior or synchronous dysplasia (P = 0.09). CONCLUSIONS: Serrated epithelial changes and sessile serrated polyps are uncommonly detected by colonoscopy in chronic ulcerative colitis and Crohn's disease patients. Histology with changes of serrated epithelium may be associated with risk of subsequent colorectal neoplasia, however further studies are needed to explore this relationship.

Baseline tumour measurements predict survival in advanced non-small cell lung cancer.

BACKGROUND: The association between tumour measurements and survival has been studied extensively in early-stage and locally advanced non-small cell lung cancer (NSCLC). We analysed these factors in patients with advanced NSCLC. METHODS: Data were derived from the E4599 trial of paclitaxel-carboplatin±bevacizumab. Associations between the Response Evaluation Criteria in Solid Tumors (RECIST) baseline sum longest diameter (BSLD), response rate, progression-free survival (PFS) and overall survival (OS) were evaluated using univariate and multivariable Cox regression models. RESULTS: A total of 759 of the 850 patients (89%) in the E4599 trial had measurable diseases and were included in this analysis. The median BSLD was 7.5 cm. BSLD predicted OS (hazard ratio (HR) 1.41; P<0.001) and had a trend towards association with PFS (HR 1.14; P=0.08). The median OS was 12.6 months for patients with BSLD <7.5 cm compared with 9.5 months for BSLD ≥ 7.5 cm. This association persisted in a multivariable model controlling multiple prognostic factors, including the presence and sites of extrathoracic disease (HR 1.24; P=0.01). There was no association between BSLD and response rate. CONCLUSION: Tumour measurements are associated with survival in the E4599 trial. If validated in other populations, this parameter may provide important prognostic information to patients and clinicians.

Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer.

BACKGROUND: Previous studies have demonstrated the efficacy and safety of bevacizumab in the treatment of non-small-cell lung cancer (NSCLC). METHODS: Summary data from randomised trials comparing first-line bevacizumab plus platinum-based chemotherapy with chemotherapy alone for inoperable locally advanced, recurrent or metastatic NSCLC were meta-analysed. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for adverse events were calculated. The chi-squared tests evaluated interactions between treatment effects, and prognostic factors and patient characteristics. RESULTS: Data of 2194 patients (1313 bevacizumab; 881 controls) from four phase II and III trials: AVF-0757g, JO19907,ECOG 4599 and AVAiL, were analysed. Compared with chemotherapy alone, bevacizumab significantly prolonged OS(HR 0.90; 95% confidence interval [CI] 0.81, 0.99; P=0.03), and PFS (0.72; 95% CI 0.66, 0.79; P<0.001). Bevacizumab showed a significantly greater effect on OS in patients with adenocarcinoma versus other histologies (P=0.03), and patients with body weight loss ≤5% versus >5% (P=0.04). Bevacizumab significantly increased the risk of grade ≥3 proteinuria, hypertension,haemorrhagic events, neutropenia, and febrile neutropenia [corrected]. CONCLUSIONS: Bevacizumab significantly prolonged OS and PFS when added to first-line platinum-based chemotherapy in patients with advanced NSCLC; no unexpected toxicity was evident.

Dual-scan acquisition for accelerated continuous-wave EPR oximetry.

Statistical analysis reveals that, given a fixed acquisition time, linewidth (and thus pO(2)) can be more precisely determined from multiple scans with different modulation amplitudes and sweep widths than from a single-scan. For a Lorentzian lineshape and an unknown but spatially uniform modulation amplitude, the analysis suggests the use of two scans, each occupying half of the total acquisition time. We term this mode of scanning as dual-scan acquisition. For unknown linewidths in a range [Γ(min), Γ(max)], practical guidelines are provided for selecting the modulation amplitude and sweep width for each dual-scan component. Following these guidelines can allow for a 3-4 times reduction in spectroscopic acquisition time versus an optimized single-scan, without requiring hardware modifications. Findings are experimentally verified using L-band spectroscopy with an oxygen-sensitive particulate probe.

Differential effect of age on survival in advanced NSCLC in women versus men: analysis of recent Eastern Cooperative Oncology Group (ECOG) studies, with and without bevacizumab.

BACKGROUND: The impact of age on prognosis in advanced stage non-small cell lung cancer (NSCLC) may differ by sex. PATIENTS AND METHODS: Eligible patients (N=1590) from E1594, a 4-arm platinum-based chemotherapy trial, and E4599 (carboplatin/paclitaxel ± bevacizumab) chemotherapy arm were divided into male and female cohorts and separated into age groups of <60 or ≥60 years old. Eligible E4599 patients (N=850) were similarly separated by age and sex and by treatment (± bevacizumab). Survival was calculated separately for each cohort. RESULTS: The median survival time (MST) for women ≥60 years old treated with chemotherapy alone on E1594 and E4599 was 11.6 months versus 9.0 months for women <60 (p=0.03). MST was 7.4 and 8.3 months for men ≥60 and <60 years old respectively (NS). In E4599 the age <60 by bevacizumab treatment interaction was statistically significant (p=0.03) for women (younger had greater benefit), with no age effect in men. CONCLUSIONS: In this unplanned, exploratory subgroup analysis of advanced stage NSCLC ECOG trials, women ≥60 years old treated with chemotherapy live longer than men and younger women. In contrast, bevacizumab survival benefit was more pronounced in men of any age and in younger women on E4599.

Multisite EPR oximetry from multiple quadrature harmonics.

Multisite continuous wave (CW) electron paramagnetic resonance (EPR) oximetry using multiple quadrature field modulation harmonics is presented. First, a recently developed digital receiver is used to extract multiple harmonics of field modulated projection data. Second, a forward model is presented that relates the projection data to unknown parameters, including linewidth at each site. Third, a maximum likelihood estimator of unknown parameters is reported using an iterative algorithm capable of jointly processing multiple quadrature harmonics. The data modeling and processing are applicable for parametric lineshapes under nonsaturating conditions. Joint processing of multiple harmonics leads to 2-3-fold acceleration of EPR data acquisition. For demonstration in two spatial dimensions, both simulations and phantom studies on an L-band system are reported.

Transretinal degeneration in ageing human retina: a multiphoton microscopy analysis.

AIM: Retinal cell remodelling has been reported as a consistent feature of ageing. However, the degree to which this results in transretinal degeneration is unclear. To address this, the authors used multiphoton microscopy to quantify retinal degeneration in post-mortem human eyes of two age groups. METHODS: Retinas from six young subjects (18-33 years old) and six older subjects (74-90 years old) were prepared as wholemount preparations. All retinas were stained with 4,6-diamidino-2-phenylindole and imaged by multiphoton confocal microscopy to quantify neuron densities in the retinal ganglion cell layer (RGCL), inner nuclear layer (INL) and outer nuclear layer (ONL). Neurons were counted using automated cell identification algorithms. All retinas were imaged hydrated to minimise tissue artefacts. RESULTS: In both groups, 56% of the area within the central 4 mm eccentricity and 27% of the area with eccentricity between 4 mm and 7 mm were imaged. Compared with young subjects, the peak RGCL neuron loss in the aged subjects (25.5%) was at 1 mm eccentricity. INL and ONL neuron densities significantly decreased at 1-2 mm eccentricity (8.7%) and 0.5-4 mm eccentricity (15.6%) respectively (P <0.05). The reduction in neuron density in the INL corresponded, spatially, to the region with the greatest neuron loss in the RGCL and ONL. CONCLUSIONS: This is the first study to correlate neurodegeneration in different populations of cells in the ageing retinas. These data confirm that the greatest neuronal loss occurs in the RGCL and ONL in human ageing retinas, whereas the INL is relatively preserved.

Oncogenic mutations regulate tumor microenvironment through induction of growth factors and angiogenic mediators.

Activating mutations in the tyrosine kinase domain of HER2 (ErbB2) have been identified in human cancers. Compared with wild-type HER2, mutant HER2 shows constitutively activate kinase activity and increased oncogenicity. Cells transformed by mutant HER2 are resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and exhibit an attenuated response to the HER2 antibody trastuzumab. We investigated herein pathways through which mutant HER2 alters the extracellular environment, potentially leading to drug resistance and the effect of simultaneously targeting HER2 and the tumor cell microenvironment with a therapeutic intent. Expression of mutant HER2 in mammary epithelial cells activated autocrine transforming growth factor (TGF) beta1 signaling through a mechanism involving Rac1 and c-Jun N-terminal kinase-activating protein 1-dependent transcription. Cells transformed by an activating mutant of H-Ras (G12V) also expressed higher TGF-beta1 level through Rac1 activation. In addition, mutant HER2 induced the EGFR ligands TGF-alpha and amphiregulin at the mRNA and protein levels. Vascular endothelial growth factor, a target of the TGF-beta-Smad transcriptional regulation, was also induced as a result of expression of mutant HER2. Inhibition of TGF-beta signaling with the Alk5 small molecule inhibitor LY2109761 reduced growth and invasiveness of cells expressing mutant HER2. Combined inhibition of intracellular and paracrine effects of mutant HER2 by trastuzumab and the EGFR antibody cetuximab were more efficient than single-agent therapies. These data suggest that mutations in oncogenes such as HER2 and Ras not only alter intracellular signaling but also influence on other components of the tumor microenvironment by inducing several pro-invasive growth factors. In turn, these serve as extracellular targets of novel therapeutic strategies directed at both cancer-driving oncogenes and the modified tumor microenvironment.

Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data.

BACKGROUND: Many randomised controlled trials have investigated the effect of adjuvant chemotherapy in operable non-small-cell lung cancer. We undertook two comprehensive systematic reviews and meta-analyses to establish the effects of adding adjuvant chemotherapy to surgery, or to surgery plus radiotherapy. METHODS: We included randomised trials, not confounded by additional therapeutic differences between the two groups and that started randomisation on or after Jan 1, 1965, which compared surgery plus adjuvant chemotherapy versus surgery alone, or surgery plus adjuvant radiotherapy and chemotherapy versus surgery plus adjuvant radiotherapy. Updated individual patient data were collected, checked, and included in meta-analyses stratified by trial. The primary endpoint was overall survival, defined as time from randomisation until death by any cause. All analyses were by intention to treat. FINDINGS: The first meta-analysis of surgery plus chemotherapy versus surgery alone was based on 34 trial comparisons and 8447 patients (3323 deaths). We recorded a benefit of adding chemotherapy after surgery (hazard ratio [HR] 0.86, 95% CI 0.81-0.92, p<0.0001), with an absolute increase in survival of 4% (95% CI 3-6) at 5 years (from 60% to 64%). The second meta-analysis of surgery plus radiotherapy and chemotherapy versus surgery plus radiotherapy was based on 13 trial comparisons and 2660 patients (1909 deaths). We recorded a benefit of adding chemotherapy to surgery plus radiotherapy (HR 0.88, 95% CI 0.81-0.97, p=0.009), representing an absolute improvement in survival of 4% (95% CI 1-8) at 5 years (from 29% to 33%). In both meta-analyses we noted little variation in effect according to the type of chemotherapy, other trial characteristics, or patient subgroup. INTERPRETATION: The addition of adjuvant chemotherapy after surgery for patients with operable non-small-cell lung cancer improves survival, irrespective of whether chemotherapy was adjuvant to surgery alone or adjuvant to surgery plus radiotherapy. FUNDING: UK Medical Research Council, Institut Gustave-Roussy, Programme Hospitalier de Recherche Clinique (AOM 05 209), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

Topography of neuron loss in the retinal ganglion cell layer in human glaucoma.

AIM: To determine if retinal ganglion cell (RGC) loss influences the loss of surrounding RGCs to generate clustered patterns of cell death in human glaucoma. It is hypothesised that retinal ganglion cell loss accelerates the loss of surrounding cells to generate, at a local, cellular scale, clustered patterns of retinal of RGC death. The absence of these interactions would result in a diffuse pattern RGC loss. METHOD: Six glaucomatous retinas (67-83 years old) and six age-matched control retinas (61-89 years old) were prepared as wholemounts and stained by 4',6-diamidino-2-phenylindole (DAPI) solution (3 microg/ml in PBS). An area corresponding to central 14 degrees of the visual field was imaged. The nearest-neighbour distribution was determined for cells in both normal and glaucomatous RGCL. RESULTS: Clustered RGC loss in human glaucoma was observed on a background of diffuse loss. The mean nearest-neighbour distance (NND) of the glaucomatous retinas was significantly higher than with controls (p<0.001). The distribution of NND in glaucomatous retinas was skewed to the higher values with a higher positive kurtosis relative to controls. The quantitative analysis of the pattern of cell loss is supported by the visual inspection of the patterns of cell loss. DISCUSSION: The nearest-neighbour analysis is consistent with the presence of two patterns of cell loss in the RGCL in glaucoma. While the diffuse of cell loss can account for an overall reduction in the RGC population, an additional non-random pattern is consistent with the hypothesis that RGC loss has a local influence on the viability of surrounding cells.

Permanent Genetic Resources added to Molecular Ecology Resources database 1 January 2009-30 April 2009.

This article documents the addition of 283 microsatellite marker loci to the Molecular Ecology Resources Database. Loci were developed for the following species: Agalinis acuta; Ambrosia artemisiifolia; Berula erecta; Casuarius casuarius; Cercospora zeae-maydis; Chorthippus parallelus; Conyza canadensis; Cotesia sesamiae; Epinephelus acanthistius; Ficedula hypoleuca; Grindelia hirsutula; Guadua angustifolia; Leucadendron rubrum; Maritrema novaezealandensis; Meretrix meretrix; Nilaparvata lugens; Oxyeleotris marmoratus; Phoxinus neogaeus; Pristomyrmex punctatus; Pseudobagrus brevicorpus; Seiridium cardinale; Stenopsyche marmorata; Tetranychus evansi and Xerus inauris. These loci were cross-tested on the following species: Agalinis decemloba; Agalinis tenella; Agalinis obtusifolia; Agalinis setacea; Agalinis skinneriana; Cercospora zeina; Cercospora kikuchii; Cercospora sorghi; Mycosphaerella graminicola; Setosphaeria turcica; Magnaporthe oryzae; Cotesia flavipes; Cotesia marginiventris; Grindelia Xpaludosa; Grindelia chiloensis; Grindelia fastigiata; Grindelia lanceolata; Grindelia squarrosa; Leucadendron coniferum; Leucadendron salicifolium; Leucadendron tinctum; Leucadendron meridianum; Laodelphax striatellus; Sogatella furcifera; Phoxinus eos; Phoxinus rigidus; Phoxinus brevispinosus; Phoxinus bicolor; Tetranychus urticae; Tetranychus turkestani; Tetranychus ludeni; Tetranychus neocaledonicus; Tetranychus amicus; Amphitetranychus viennensis; Eotetranychus rubiphilus; Eotetranychus tiliarium; Oligonychus perseae; Panonychus citri; Bryobia rubrioculus; Schizonobia bundi; Petrobia harti; Xerus princeps; Spermophilus tridecemlineatus and Sciurus carolinensis.

Predicting gene promoter methylation in non-small-cell lung cancer by evaluating sputum and serum.

The use of 5-methylcytosine demethylating agents in conjunction with inhibitors of histone deacetylation may offer a new therapeutic strategy for lung cancer. Monitoring the efficacy of gene demethylating treatment directly within the tumour may be difficult due to tumour location. This study determined the positive and negative predictive values of sputum and serum for detecting gene methylation in primary lung cancer. A panel of eight genes was evaluated by comparing methylation detected in the primary tumour biopsy to serum and sputum obtained from 72 patients with Stage III lung cancer. The prevalence for methylation of the eight genes in sputum (21-43%) approximated to that seen in tumours, but was 0.7-4.3-fold greater than detected in serum. Sputum was superior to serum in classifying the methylation status of genes in the tumour biopsy. The positive predictive value of the top four genes (p16, DAPK, PAX5 beta, and GATA5) was 44-72% with a negative predictive value for these genes > or =70%. The highest specificity was seen for the p16 gene, and this was associated with a odds ratio of six for methylation in the tumour when this gene was methylated in sputum. In contrast, for serum, the individual sensitivity for all genes was 6-27%. Evaluating the combined effect of methylation of at least one of the four most significant genes in sputum increased the positive predictive value to 86%. These studies demonstrate that sputum can be used effectively as a surrogate for tumour tissue to predict the methylation status of advanced lung cancer where biopsy is not feasible.

Impact of hemoglobin levels on outcomes of adjuvant chemotherapy in resected non-small cell lung cancer: the JBR.10 trial experience.

BACKGROUND: Cisplatin-induced anemia may correlate with adverse events, poor quality of life (QoL), decreased adjuvant chemotherapy (ACT) dose intensity, shorter relapse-free survival (RFS) or overall survival (OS). METHODS: The JBR.10 trial demonstrated significantly longer survival with adjuvant cisplatin and vinorelbine (n=242) compared to observation (n=240) in patients with resected NSCLC [Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005;352(25):2640-2]. This exploratory analysis evaluates the predictive value of baseline (in all patients) and during-treatment (in ACT arm only) hemoglobin (Hb) levels on OS and RFS when adjusted for prognostic factors. Baseline (in all patients) and during treatment (in ACT arm only) Hb levels were also correlated with adverse events, QoL, morbidity and ACT dose intensity. RESULTS: Baseline Hb did not predict RFS or OS. However, there was a trend to shorter OS (p=0.1) when baseline Hb was <120g/L. Lower baseline Hb predicted increased hospitalization (p=0.04) and worse QoL (SOB item, p=0.03) but had no impact on adverse events or dose intensity. There was a trend to longer RFS (p=0.08) in patients with lower nadir during-treatment Hb and to longer OS (p=0.06) and RFS (p=0.08) in patients with maximum during-treatment Hb drop >30% that was not maintained when ACT dose intensity was included in the model. Maximum during-treatment Hb drop >30% correlated with increased lethargy (p=0.003) and worse QoL (fatigue item, p=0.07). CONCLUSIONS: Lower baseline and during-treatment Hb levels seem associated with poorer QoL, fatigue and increased hospitalization. There is a trend for shorter OS in patients with lower baseline Hb levels.

Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer.

BACKGROUND: R115777 (tipifarnib, Zarnestra) is a farnesyl transferase inhibitor that blocks the farnesylation of proteins involved in signal transduction pathways critical for cell proliferation and survival. This multicenter phase II study was conducted to determine the efficacy, tolerability and pharmacokinetics of R115777 in patients with relapsed small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients who had a partial or complete response to their initial chemotherapy regimen, followed by at least 3 months off treatment before relapse (sensitive relapse) were eligible. R115777 was administered in 3-week cycles at a dose of 400 mg orally twice daily for 14 consecutive days followed by 7 days off treatment. RESULTS: Twenty-two patients were enrolled. The median progression-free survival was 1.4 months and median overall survival was 6.8 months. Non-hematological toxicities were predominantly grade 1-2 and included nausea (64%) and fatigue (60%). Grade 3-4 granulocytopenia and thrombocytopenia occurred in 27% and 23% of patients, respectively. Febrile neutropenia was not observed. Pharmacokinetic studies demonstrated peak plasma concentrations of R115777 2.6-4.5 h after oral dosing and no significant drug accumulation. The trial was terminated because no objective responses were observed in 20 patients evaluable for response. CONCLUSIONS: R115777 showed no significant antitumor activity as a single agent in sensitive-relapse SCLC.

Docetaxel combined with trastuzumab is an active regimen in HER-2 3+ overexpressing and fluorescent in situ hybridization-positive metastatic breast cancer: a multi-institutional phase II trial.

PURPOSE: To determine the efficacy and safety of weekly docetaxel and trastuzumab as first- or second-line therapy in women with HER-2-overexpressing metastatic breast cancer and to correlate the efficacy of trastuzumab with HER-2 status as determined by immunohistochemistry assay and fluorescent in situ hybridization (FISH). PATIENTS AND METHODS: Twenty-six women with HER-2-positive (HercepTest [Dako Corp, Carpenteria, CA]2 to 3+) metastatic breast cancer were enrolled onto this study of trastuzumab (4 mg/kg load; 2 mg/kg/wk administered intravenously) and docetaxel (35 mg/m2/wk for 6 weeks). RESULTS: Using an intent-to-treat analysis, the overall response rate was 50% (13 of 26 patients). Eight patients (31%) had a period of stable disease posttherapy. Among HER-2 3+ patients, the overall response rate was 63% (12 of 19 patients) compared with a 14% response rate (one of seven patients) for HER-2 2+ patients (P=.07). Patients with FISH-positive tumors experienced an overall response rate of 64%. Median time to progression was 12.4 months for the entire cohort (HER-2 3+ tumors, 12.3 months; HER-2 2+ lesions, 9.5 months) and median survival was 22.1 months. All HER-2 3+ patients were FISH-positive; the only HER-2 2+ patient responding to treatment was also FISH-positive. Grade 4 toxicities occurred in four patients; most toxicities were mild. CONCLUSION: Trastuzumab plus docetaxel is an active and well-tolerated regimen in women with HER-2 3+ overexpressing or FISH-positive metastatic breast cancer.

Visual responses of crayfish ocular motoneurons: an information theoretical analysis.

Motoneuron responses were elicited by global visual motion and stepwise displacements of an illuminated stripe. Stimulus protocols were identical to those used in previous behavioral studies of compensatory eyestalk reflexes. The firing rates and directional selectivity of the motoneuron responses were measured with respect to four stimulus dimensions (spatial frequency, contrast, angular displacement and velocity). The directional selectivity of the motoneuron response was correlated to the previously measured gain of the reflex for each stimulus dimension. The information theoretical analysis is based upon Kullback-Leibler (K-L) distances which measure the dissimilarity of responses to different stimuli. K-L distances for single neurons are strongly influenced by the mean rate difference of the responses to any pair of stimuli. Because of redundancy, the joint K-L distances of pairs of neurons were less than the sum of the K-L distances of the individual neurons. Furthermore, the joint K-L distances were only weakly influenced by correlations among coactivated neurons. For most of the stimulus dimensions, the K-L distances of single motoneurons were not sufficient to account for the stimulus discriminations exhibited by the eyestalk reflex which typically required the summed output of 2 to 5 motoneurons. Thus the behaviorally relevant information is encoded in the motoneuron ensemble. The minimum time required to discriminate the direction of motion (the encoding window) for a single motoneuron is about 380 to 480 ms (including a 175 ms response latency) for stepwise displacements and up to 1.0 s for global motion. During this period a motoneuron fires 2 to 3 impulses.

Mortality during hospitalisation for pneumonia in Alberta, Canada, is associated with physician volume.

The association of mortality with patient factors (severity of illness, comorbidity), physician factors (specialty training, prehospitalisation visit, in-hospital consultation, volume of patients seen per physician) and healthcare organisation factors (patient-travel distances, regional beds per capita, admitting hospital-bed occupancy, admitting hospital-bed turnover, hospital location, volume of pneumonia cases per hospital) after hospital admission with community-acquired pneumonia was investigated using administrative data from Alberta, Canada from April 1, 1994-March 31, 1999. During the 5-yr study period there were 43,642 pneumonia hospitalisations, with an 11% in-hospital and 26% 1-yr mortality. Patient severity of illness and comorbidity were the strongest predictors of increased mortality. Physicians with the highest in-hospital pneumonia patient volume (>27 patients x yr(-1)) cared for patients with greater severity/comorbidity, but with decreased odds of in-hospital mortality, compared with the lowest volume physicians (less than seven patients per year). The effects of internal medicine specialist or subspecialist care were mixed, with a reduction in deaths for the first 72 h and an increase in in-hospital deaths. Prehospitalisation visit by a physician was associated with decreased mortality. Healthcare organisation factors were the least strong predictor of mortality, demonstrating an effect only for 1-yr mortality in those discharged alive from hospital. Admissions to larger volume or metropolitan hospitals were associated with a decrease in mortality. Severity of illness and comorbidity had the strongest association with mortality. The first association of high-volume physician and pre-hospital care with decreased in-hospital mortality for community-acquired pneumonia is reported.

[Physiology of aqueous humor outflow resistance: its relation to giant vacuoles]. / Actualités sur la physiologie de la résistance à l'écoulement de l'humeur aqueuse: rôle des vacuoles géantes.

About 2% of the French population over the age of 40 suffers from open angle glaucoma, a disorder for which ocular hypertension is the main risk factor. Improving our understanding of primary open-angle glaucoma physiopathology has been an area of intense research for nearly a century. The main aqueous outflow system in the human eye includes the trabecular meshwork, Schlemm's canal, aqueous veins, and the episcleral veins. Schlemm's canal is bordered by endothelium cells, many of which contain giant vacuoles, structures that are sensitive to intraocular pressure and that therefore can act as markers of active outflow. Giant vacuoles are most often found near collector channels in normal eyes, probably in areas of low downstream pressure. In the glaucoma eye, determining where giant vacuoles form could help localize the site of pathological outflow resistance.