Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX) : an open-label randomised phase III trial

Background: Use of cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has the potential to increase survival in patients with advanced non-small-cell lung cancer. We therefore compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced EGFR-positive non-small-cell lung cancer. Methods: In a multinational, multicentre, open-label, phase III trial, chemotherapy-naive patients (≥18 years) with advanced EGFR-expressing histologically or cytologically proven stage wet IIIB or stage IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio to chemotherapy plus cetuximab or just chemotherapy. Chemotherapy was cisplatin 80 mg/m 2 intravenous infusion on day 1, and vinorelbine 25 mg/m 2 intravenous infusion on days 1 and 8 of every 3-week cycle) for up to six cycles. Cetuximab-at a starting dose of 400 mg/m 2 intravenous infusion over 2 h on day 1, and from day 8 onwards at 250 mg/m 2 over 1 h per week-was continued after the end of chemotherapy until disease progression or unacceptable toxicity had occurred. The primary endpoint was overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00148798. Findings: Between October, 2004, and January, 2006, 1125 patients were randomly assigned to chemotherapy plus cetuximab (n=557) or chemotherapy alone (n=568). Patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group (median 11·3 months vs 10·1 months; hazard ratio for death 0·871 [95% CI 0·762-0·996]; p=0·044). The main cetuximab-related adverse event was acne-like rash (57 [10%] of 548, grade 3). Interpretation: Addition of cetuximab to platinum-based chemotherapy represents a new treatment option for patients with advanced non-small-cell lung cancer. Funding: Merck KGaA. © 2009 Elsevier Ltd. All rights reserved.

Tumour necrosis is an independent prognostic marker in non-small cell lung cancer : correlation with biological variables

Background Tumour necrosis (TN) is recognized to be a consequence of chronic cellular hypoxia. TN and hypoxia correlate with poor prognosis in solid tumours. Methods In a retrospective study the prognostic implications of the extent of TN was evaluated in non-small cell lung cancer (NSCLC) and correlated with clinicopathological variables and expression of epidermal growth factor receptor, Bcl-2, p53 and matrix metalloproteinase-9 (MMP-9). Tissue specimens from 178 surgically resected cases of stage I-IIIA NSCLC with curative intent were studied. The specimens were routinely processed, formalin-fixed and paraffin-embedded. TN was graded as extensive or either limited or absent by two independent observers; disagreements were resolved using a double-headed microscope. The degree of reproducibility was estimated by re-interpreting 40 randomly selected cases after a 4 month interval. Results Reproducibility was attained in 36/40 cases, Kappa score=0.8 P<0.001. TN correlated with T-stage (P=0.001), platelet count (P=0.004) and p53 expression (P=0.031). Near significant associations of TN with N-stage (P=0.063) and MMP-9 expression (P=0.058) were seen. No association was found with angiogenesis (P=0.98). On univariate (P=0.0016) and multivariate analysis (P=0.023) TN was prognostic. Conclusion These results indicate that extensive TN reflects an aggressive tumour phenotype in NSCLC and may improve the predictive power of the TMN staging system. The lack of association between TN and angiogenesis may be important although these variables were not evaluated on serial sections. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

Measuring dietary intake in remote Australian Aboriginal communities

This paper reports a comparison of the practicality, acceptability and face validity of five dietary intake methods in two remote Australian Aboriginal communities: weighed dietary intake, 24‐hour recall, ‘store‐turnover’, diet history and food frequency methods. The methods used to measure individual dietary intake were poorly accepted by the communities. Quantitative data were obtained only from the first three methods. The 24‐hour recall method tended to produce higher nutrient intakes than the weighed intake method and certain foods appeared to be selectively recalled according to perceived nutritional desirability. The ‘store‐turnover’ method was most acceptable to the communities and had less potential for bias than the other methods. It was also relatively objective, non‐intrusive, rapid, easy and inexpensive. However, food distribution patterns within the communities could not be assessed by this method. Nevertheless, other similarly isolated communities may benefit by use of the ‘store‐turnover’ method.

Modeling predictors of risky drug use behavior among male street laborers in urban Vietnam

Background The application of theoretical frameworks for modeling predictors of drug risk among male street laborers remains limited. The objective of this study was to test a modified version of the IMB (Information-Motivation-Behavioral Skills Model), which includes psychosocial stress, and compare this modified version with the original IMB model in terms of goodness-of-fit to predict risky drug use behavior among this population. Methods In a cross-sectional study, social mapping technique was conducted to recruit 450 male street laborers from 135 street venues across 13 districts of Hanoi city, Vietnam, for face-to-face interviews. Structural equation modeling (SEM) was used to analyze data from interviews. Results Overall measures of fit via SEM indicated that the original IMB model provided a better fit to the data than the modified version. Although the former model was able to predict a lesser variance than the latter (55% vs. 62%), it was of better fit. The findings suggest that men who are better informed and motivated for HIV prevention are more likely to report higher behavioral skills, which, in turn, are less likely to be engaged in risky drug use behavior. Conclusions This was the first application of the modified IMB model for drug use in men who were unskilled, unregistered laborers in urban settings. An AIDS prevention program for these men should not only distribute information and enhance motivations for HIV prevention, but consider interventions that could improve self-efficacy for preventing HIV infection. Future public health research and action may also consider broader factors such as structural social capital and social policy to alter the conditions that drive risky drug use among these men.

Raising awareness of Australian Aboriginal peoples reality : Embedding Aboriginal knowledge in social work education through the use of field experiences

Effective social work practice with Aboriginal peoples and communities requires knowledge of operational communication skills and practice methods. In addition, there is also a need for practitioners to be aware of the history surrounding white engagement with Aboriginal communities and their cultures. Indeed, the Australian Association of Social Workers (AASW) acknowledges the importance of social workers practising cultural safety. Engendering knowledge of cultural safety for social work students is the opportunity to listen and talk with Aboriginal people who have experienced the destructive impacts of colonisation and the subsequent disruption to family and community. This article discusses the use of field experiences within a Masters of Social Work (Qualifying) Program (MSW) as an educational method aimed at increasing student awareness of contemporary Aboriginal issues and how to practice effectively and within a culturally safe manner.

Stored blood products augment inflammation in a two-event model of Transfusion Related Acute Lung Injury (TRALI)

Aim/Background TRALI is hypothesised to develop via a two-event mechanism involving both the patieint's underlying morbidity and blood product factors. The storage of cellular products has been implicated in cases of non-antibody mediated TRALI, however the pathophysiological mechanisms are undefined. We investigated blood product storage-related modulation of inflmmatory cells and medicators involved in TRALI. Methods In an in vitro mode, fresh human whole blood was mixed with culture media (control) or LPS as a 1st event and "transfused" with 10% (v/v) pooled supernatant (SN) from Day 1 (d1, n=75) or Day 42 (D42, n=113) packed red blood cells (PRBCs) as a 2nd event. Following 6hrs, culture SN was used to assess the overall inflammatory response (cytometric bead array) and a duplicate assay containing protein transport inhibitor was used to assess neutrophil- and monocyte-specific inflmamatory responses using multi-colour flow cytometry. Panels: IL-6, IL-8, IL-10, IL-12, IL-1, TNF, MCP-1, IP-10, MIP-1. One-way ANOVA 95% CI. Results In the absence of LPS, exposure to D1 or D42 PRBC-SN reduced monocyte expression of IL-6, IL-8 and Il-10. D42 PRBC-SN also reduced monocyte IP-10, and the overall IL-8 production was increased. In the presence of LPS, D1-PRBC SN only modified overall IP-10 levels which were reduced. However, cf LPS alone, the combination of LPS and D42 PRBC-SN resulted in increased neutrophil and monocyte productionof IL-1 and IL-8 as well as reduced monocyte TNF production. Additionally, LPS and D42 PRBC-SN resulted in overall inflmmatory changes: elevated IL-8, In the absence of LPS, exposure to both fresh and stored PRBC-SN predominantly resulted in an anti-imflammatory response. However, in the presence of LPS, stored but not fresh PRBC-SN augmented a pro-inflammatory profile. These data support the two-event mechanism of TRALI pathogenesis, and highlights blood product storage duration as a factor contributing to the development of inflmamatory responses in non-antibody mediated TRALI.

Comparing methods for modelling spreading cell fronts

Spreading cell fronts play an essential role in many physiological processes. Classically, models of this process are based on the Fisher-Kolmogorov equation; however, such continuum representations are not always suitable as they do not explicitly represent behaviour at the level of individual cells. Additionally, many models examine only the large time asymptotic behaviour, where a travelling wave front with a constant speed has been established. Many experiments, such as a scratch assay, never display this asymptotic behaviour, and in these cases the transient behaviour must be taken into account. We examine the transient and asymptotic behaviour of moving cell fronts using techniques that go beyond the continuum approximation via a volume-excluding birth-migration process on a regular one-dimensional lattice. We approximate the averaged discrete results using three methods: (i) mean-field, (ii) pair-wise, and (iii) one-hole approximations. We discuss the performace of these methods, in comparison to the averaged discrete results, for a range of parameter space, examining both the transient and asymptotic behaviours. The one-hole approximation, based on techniques from statistical physics, is not capable of predicting transient behaviour but provides excellent agreement with the asymptotic behaviour of the averaged discrete results, provided that cells are proliferating fast enough relative to their rate of migration. The mean-field and pair-wise approximations give indistinguishable asymptotic results, which agree with the averaged discrete results when cells are migrating much more rapidly than they are proliferating. The pair-wise approximation performs better in the transient region than does the mean-field, despite having the same asymptotic behaviour. Our results show that each approximation only works in specific situations, thus we must be careful to use a suitable approximation for a given system, otherwise inaccurate predictions could be made.

Applying quantile regression for modeling equivalent property damage only crashes to identify accident blackspots

Hot spot identification (HSID) aims to identify potential sites—roadway segments, intersections, crosswalks, interchanges, ramps, etc.—with disproportionately high crash risk relative to similar sites. An inefficient HSID methodology might result in either identifying a safe site as high risk (false positive) or a high risk site as safe (false negative), and consequently lead to the misuse the available public funds, to poor investment decisions, and to inefficient risk management practice. Current HSID methods suffer from issues like underreporting of minor injury and property damage only (PDO) crashes, challenges of accounting for crash severity into the methodology, and selection of a proper safety performance function to model crash data that is often heavily skewed by a preponderance of zeros. Addressing these challenges, this paper proposes a combination of a PDO equivalency calculation and quantile regression technique to identify hot spots in a transportation network. In particular, issues related to underreporting and crash severity are tackled by incorporating equivalent PDO crashes, whilst the concerns related to the non-count nature of equivalent PDO crashes and the skewness of crash data are addressed by the non-parametric quantile regression technique. The proposed method identifies covariate effects on various quantiles of a population, rather than the population mean like most methods in practice, which more closely corresponds with how black spots are identified in practice. The proposed methodology is illustrated using rural road segment data from Korea and compared against the traditional EB method with negative binomial regression. Application of a quantile regression model on equivalent PDO crashes enables identification of a set of high-risk sites that reflect the true safety costs to the society, simultaneously reduces the influence of under-reported PDO and minor injury crashes, and overcomes the limitation of traditional NB model in dealing with preponderance of zeros problem or right skewed dataset.

Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations

Purpose The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS). Patients and Methods In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs). Results A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatmentrelated adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain. Conclusion Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

Increased tubulointerstitial recruitment of human CD141(hi) CLEC9A(+) and CD1c(+) myeloid dendritic cell subsets in renal fibrosis and chronic kidney disease

Dendritic cells (DCs) play critical roles in immune-mediated kidney diseases. Little is known, however, about DC subsets in human chronic kidney disease, with previous studies restricted to a limited set of pathologies and to using immunohistochemical methods. In this study, we developed novel protocols for extracting renal DC subsets from diseased human kidneys and identified, enumerated, and phenotyped them by multicolor flow cytometry. We detected significantly greater numbers of total DCs as well as CD141(hi) and CD1c(+) myeloid DC (mDCs) subsets in diseased biopsies with interstitial fibrosis than diseased biopsies without fibrosis or healthy kidney tissue. In contrast, plasmacytoid DC numbers were significantly higher in the fibrotic group compared with healthy tissue only. Numbers of all DC subsets correlated with loss of kidney function, recorded as estimated glomerular filtration rate. CD141(hi) DCs expressed C-type lectin domain family 9 member A (CLEC9A), whereas the majority of CD1c(+) DCs lacked the expression of CD1a and DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN), suggesting these mDC subsets may be circulating CD141(hi) and CD1c(+) blood DCs infiltrating kidney tissue. Our analysis revealed CLEC9A(+) and CD1c(+) cells were restricted to the tubulointerstitium. Notably, DC expression of the costimulatory and maturation molecule CD86 was significantly increased in both diseased cohorts compared with healthy tissue. Transforming growth factor-β levels in dissociated tissue supernatants were significantly elevated in diseased biopsies with fibrosis compared with nonfibrotic biopsies, with mDCs identified as a major source of this profibrotic cytokine. Collectively, our data indicate that activated mDC subsets, likely recruited into the tubulointerstitium, are positioned to play a role in the development of fibrosis and, thus, progression to chronic kidney disease.

Stimulating organizational ingenuity with design methods

Organizations invest in ways to stimulate new ideas for new products and services for the benefit of the organization, engaging in tournaments and competitions to generate new ideas or to combine existing ideas in new ways for new products and services (Terweisch and Uhlrich, 2009). Specifically, some large companies have developed platforms for posting intractable problems to tap into the ideas and problem solving abilities of a broader range of people (Huston and Sakkab, 2006; Morgan and Wang, 2010), and to develop new and elegant solutions often in an open innovation approach (Chesbrough, 2003). The notion of ingenuity is often applied to individuals who create innovative solutions in situations of constraint, where ingenuity in the form of elegant solutions can be understood as one form of resourcefulness (Young, 2011). However, the notion of organizational ingenuity locates ingenuity more centrally to an organization's strategic decision making and implementation, embedding ingenuity into the company's culture. Studies of organizations displaying ingenuity indicate a range of possibilities from extreme ingenuity (Baker and Nelson, 2005) to less dramatic but substantial changes (Thomke, 2003), sometimes in an experimental phase or as part of a move towards a new and distinct identity for ongoing innovation.

Geometric sensitivity of patient-specific finite element models of the spine to variability in user-selected anatomical landmarks

Software to create individualised finite element (FE) models of the osseoligamentous spine using pre-operative computed tomography (CT) data-sets for spinal surgery patients has recently been developed. This study presents a geometric sensitivity analysis of this software to assess the effect of intra-observer variability in user-selected anatomical landmarks. User-selected landmarks on the osseous anatomy were defined from CT data-sets for three scoliosis patients and these landmarks were used to reconstruct patient-specific anatomy of the spine and ribcage using parametric descriptions. The intra-observer errors in landmark co-ordinates for these anatomical landmarks were calculated. FE models of the spine and ribcage were created using the reconstructed anatomy for each patient and these models were analysed for a loadcase simulating clinical flexibility assessment. The intra-observer error in the anatomical measurements was low in comparison to the initial dimensions, with the exception of the angular measurements for disc wedge and zygapophyseal joint (z-joint) orientation and disc height. This variability suggested that CT resolution may influence such angular measurements, particularly for small anatomical features, such as the z-joints, and may also affect disc height. The results of the FE analysis showed low variation in the model predictions for spinal curvature with the mean intra-observer variability substantially less than the accepted error in clinical measurement. These findings demonstrate that intra-observer variability in landmark point selection has minimal effect on the subsequent FE predictions for a clinical loadcase.

Age and gender differences in objectively measured physical activity in youth

Purpose The purpose of this study was to evaluate age and gender differences in objectively measured physical activity (PA) in a population-based sample of students in grades 1–12. Methods Participants (185 male, 190 female) wore a CSA 7164 accelerometer for 7 consecutive days. To examine age-related trends, students were grouped as follows: grades 1–3 (N = 90), grades 4–6 (N = 91), grades 7–9 (N = 96), and grades 10–12 (N = 92). Bouts of PA and minutes spent in moderate-to-vigorous PA (MVPA) and vigorous PA (VPA) were examined. Results Daily MVPA and VPA exhibited a significant inverse relationship with grade level, with the largest differences occurring between grades 1–3 and 4–6. Boys were more active than girls; however, for overall PA, the magnitudes of the gender differences were modest. Participation in continuous 20-min bouts of PA was low to nonexistent. Conclusion Our results support the notion that PA declines rapidly during childhood and adolescence and that accelerometers are feasible alternatives to self-report methods in moderately sized population-level surveillance studies.

Associations between physical activity and other health behaviors in a representative sample of US adolescents

OBJECTIVES This study examined the associations between physical activity and other health behaviors in a representative sample of US adolescents. METHODS In the 1990 Youth Risk Behavior Survey, 11631 high school students provided information on physical activity; diet; substance use; and other negative health behaviors. Logistic regression analyses examined associations between physical activity and other health behaviors in a subset of 2652 high-active and 1641 low-active students. RESULTS Low activity was associated with cigarette smoking, marijuana use, lower fruit and vegetable consumption, greater television watching, failure to wear a seat belt, and low perception of academic performance. For consumption of fruit, television watching, and alcohol consumption, significant interactions were found with race/ethnicity or sex, suggesting that sociocultural factors may affect the relationships between physical activity and some health behaviors. CONCLUSIONS Low physical activity was associated with several other negative health behaviors in teenagers. Future studies should examine whether interventions for increasing physical activity in youth can be effective in reducing negative health behaviors.