A randomised, concentration-controlled, comparison of standard (5-day) vs. prolonged (15-day) infusions of etoposide phosphate in small-cell lung cancer

Purpose: This randomised trial was designed to investigate the activity and toxicity of continuous infusion etoposide phosphate (EP), targeting a plasma etoposide concentration of either 3 μg/ml for five days (5d) or 1 μg/ml for 15 days (15d), in previously untreated SCLC patients with extensive disease. Patients and methods: EP was used as a single agent. Plasma etoposide concentration was monitored on days 2 and 4 in patients receiving 5d EP and on days 2, 5, 8 and 11 in patients receiving 15d EP, with infusion modification to ensure target concentrations were achieved. Treatment was repeated every 21 days for up to six cycles, with a 25% reduction in target concentration in patients with toxicity. Results: The study has closed early after entry of 29 patients (14 with 5d EP, 15 with 15d EP). Objective responses were seen in seven of 12 (58%, confidence interval (CI): 27%-85%) evaluable patients after 5d EP, and two of 14 (14%, CI: 4%42%) evaluable patients after 15d EP (P = 0.038). Grade 3 or 4 neutropenia or leucopenia during the first cycle of treatment was observed in six of 12 patients after 5d EP and 0/14 patients after 15d EP (P = 0.004), with median nadir WBC count of 2.6 x 109/1 after 5d and 5.0 x 109/1 after 15d EP (P = 0.017). Only one of 49 cycles of 15d EP was associated with grade 3 or worse haematological toxicity, compared to 14 of 61 cycles of 5d EP. Conclusions: Although the number of patients entered into this trial was small, the low activity seen at 1 μg/ml in the 15d arm suggests that this concentration is below the therapeutic window in this setting. Further concentration- controlled studies with prolonged EP infusions are required.

bcl-2 and c-erbB-2 proteins are involved in the regulation of VEGF and of thymidine phosphorylase angiogenic activity in non-small-cell lung cancer

Tumour angiogenesis has been recently recognised as one of the most important prognostic factors in lung cancer. Although a variety of angiogenic factors have been identified, the angiogenesis process remains poorly understood. Bcl-2, c-erbB-2 and p53 are well-known oncogenes involved in non- small-cell lung cancer pathogenesis. A direct correlation of thymidine phosphorylase (TP) and of vascular endothelial growth factor (VEGF) with intratumoural angiogenesis has been reported. In the present study we investigated the possible regulatory role if bcl-2, c-erB-2 proteins in angiogenesis and in VEGF and TP expression in non-small-cell lung cancer. Two hundred sixteen specimens from T1,2-NO, 1 staged patients treated with surgery alone were immunohistochemically examined. Bcl-2 and c-erbB-2 were significantly inversely related to each other (P = 0.04) and both were inversely associated with microvessel density (P < 0.02). High TP and VEGF reactivity was statistically related to loss of bcl-2 expression (P < 0.01). A significant co-expression of c-erbB-2 with TP was noted (P = 0.01). However, TP expression was related to high angiogenesis only in cases with absence of c-erB-2 expression (P < 0.0001). c-erbB-2 expression in poorly vascularised tumours was linked with poor outcome (P = 0.03). The present study provides strong evidence that the bcl-2 gene has a suppressive function over genes involved in both angiogenesis (VEGF and TP) and cell migration (c- erbB-2) in NSCLC. TP and c-erbB-2 proteins are significantly, and often simultaneously, expressed in bcl-2 negative cases. However, expression of the c-erbB-2 abolishes the TP-related angiogenic activity. Whether this is a result of a direct activity of the c-erbB-2 protein or a consequence of a c- erbB-2-related immune response remains to be further investigated.

Reduced biceps femoris myoelectrical activity influences eccentric knee flexor weakness after repeat sprint running

The aim of this study was to determine whether declines in knee flexor strength following overground repeat sprints were related to changes in hamstrings myoelectrical activity. Seventeen recreationally active males completed maximal isokinetic concentric and eccentric knee flexor strength assessments at 1800.s-1 before and after repeat sprint running. Myoelectrical activity of the biceps femoris (BF) and medial hamstrings (MH) was measured during all isokinetic contractions. Repeated measures mixed model (Fixed factors = time [pre- and post- repeat sprint] and leg [dominant and non-dominant], random factor = participants) design was fitted with the restricted maximal likelihood method. Repeat sprint running resulted in significant declines in eccentric, and concentric, knee flexor strength (eccentric = 25 ± 34 Nm, 15% p<0.001; concentric 11 Nm± 22 Nm, 10% p = 0.001). Eccentric BF myoelectrical activity was significantly reduced (10%; p= 0.033). Concentric BF and all MH myoelectrical activity were not altered. The declines in maximal eccentric torque were associated with the change in eccentric biceps femoris myoelectrical activity (p = 0.013). Following repeat sprint running there were preferential declines in the myoelectrical activity of the BF, which explained declines in eccentric knee flexor strength.

Continuous remote emissions monitoring – the lynchpin for air quality management

Diesel particulate matter (DPM), in particular, has been likened in a somewhat inflammatory manner to be the ‘next asbestos’. From the business change perspective, there are three areas holding the industry back from fully engaging with the issue: 1. There is no real feedback loop in any operational sense to assess the impact of investment or application of controls to manage diesel emissions. 2. DPM are getting ever smaller and more numerous, but there is no practical way of measuring them to regulate them in the field. Mass, the current basis of regulation, is becoming less and less relevant. 3. Diesel emissions management is generally wholly viewed as a cost, yet there are significant areas of benefit available from good management. This paper discusses a feedback approach to address these three areas to move the industry forward. The six main areas of benefit from providing a feedback loop by continuously monitoring diesel emissions have been identified: 1. Condition-based maintenance. Emissions change instantaneously if engine condition changes. 2. Operator performance. An operator can use a lot more fuel for little incremental work output through poor technique or discipline. 3. Vehicle utilisation. Operating hours achieved and ratios of idling to under power affect the proportion of emissions produced with no economic value. 4. Fuel efficiency. This allows visibility into other contributing configuration and environmental factors for the vehicle. 5. Emission rates. This allows scope to directly address the required ratio of ventilation to diesel emissions. 6. Total carbon emissions - for NGER-type reporting requirements, calculating the emissions individually from each vehicle rather than just reporting on fuel delivered to a site.

Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer

Background: The Lung Cancer Cetuximab Study is an open-label, randomized phase II pilot study of cisplatin and vinorelbine combined with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody cetuximab versus cisplatin and vinorelbine alone, in patients with advanced EGFR-expressing, non-small-cell lung cancer (NSCLC). End points of the study are activity, safety and pharmacokinetics. Patients and methods: Following randomization, for a maximum of eight cycles, patients received three-weekly cycles of cisplatin (80 mg/m2, day 1) and vinorelbine (25 mg/m2 on days 1 and 8) alone or following cetuximab treatment (initial dose 400 mg/m, followed by 250 mg/m2 weekly thereafter). Results: Eighty-six patients were randomly allocated to the study (43 per arm). Confirmed response rates were 28% in the cisplatin/vinorelbine arm (A) and 35% in the cetuximab plus cisplatin/vinorelbine arm (B). Median progression-free survival (PFS) was 4.6 months in arm A and 5.0 months in arm B, with PFS rates at 12 months of 0% and 15%, respectively. Median survival was 7.3 months in arm A and 8.3 months in arm B. The 24-month survival rates were 0% and 16%, respectively. The cetuximab combination was well tolerated. Conclusion: In the first-line treatment of advanced NSCLC, the combination of cetuximab plus cisplatin/vinorelbine demonstrated an acceptable safety profile and the potential to improve activity over cisplatin/vinorelbine alone. © 2007 European Society for Medical Oncology.

Effective technologies for noninvasive remote monitoring in heart failure

Background Trials of new technologies to remotely monitor for signs and symptoms of worsening heart failure are continually emerging. The extent to which technological differences impact the effectiveness of non-invasive remote monitoring for heart failure management is unknown. Objective To examine the effect of specific technology used for non-invasive remote monitoring of people with heart failure on all-cause mortality and heart failure-related hospitalisations. Methods A sub-analysis of a large systematic review and meta-analysis was conducted. Studies were stratified according to the specific type of technology used and separate meta-analyses were performed. Four different types of non-invasive remote monitoring technologies were identified including structured telephone calls, videophone, interactive voice response devices and telemonitoring. Results Only structured telephone calls and telemonitoring were effective in reducing the risk of all-cause mortality (RR 0.87; 95% CI=0.75-1.01; p=0.06 and 0.62; 95% CI=0.50-0.77; p<0.0001) and heart failure-related hospitalisations (RR 0.77; 95% CI=0.68-0.87; p<0.001) and 0.75; 95% CI=0.63-0.91; p=0.003). More research data is required for videophone and interactive voice response technologies. Conclusions This sub-analysis identified that only two of the four specific technologies used for non-invasive remote monitoring in heart failure improved outcomes. When results of studies that involved these disparate technologies were combined in previous meta-analyses, significant improvements in outcomes were identified. As such, this study has highlighted implications for future meta-analyses of randomised controlled trials focused on evaluating the effectiveness of remote monitoring in heart failure.

Monitoring the price and affordability of foods and diets globally

Food prices and food affordability are important determinants of food choices, obesity and non-communicable diseases. As governments around the world consider policies to promote the consumption of healthier foods, data on the relative price and affordability of foods, with a particular focus on the difference between ‘less healthy’ and ‘healthy’ foods and diets, are urgently needed. This paper briefly reviews past and current approaches to monitoring food prices, and identifies key issues affecting the development of practical tools and methods for food price data collection, analysis and reporting. A step-wise monitoring framework, including measurement indicators, is proposed. ‘Minimal’ data collection will assess the differential price of ‘healthy’ and ‘less healthy’ foods; ‘expanded’ monitoring will assess the differential price of ‘healthy’ and ‘less healthy’ diets; and the ‘optimal’ approach will also monitor food affordability, by taking into account household income. The monitoring of the price and affordability of ‘healthy’ and ‘less healthy’ foods and diets globally will provide robust data and benchmarks to inform economic and fiscal policy responses. Given the range of methodological, cultural and logistical challenges in this area, it is imperative that all aspects of the proposed monitoring framework are tested rigorously before implementation.

INFORMAS (International Network for Food and Obesity/non-communicable diseases Research, Monitoring and Action Support) : overview and key principles

Non-communicable diseases (NCDs) dominate disease burdens globally and poor nutrition increasingly contributes to this global burden. Comprehensive monitoring of food environments, and evaluation of the impact of public and private sector policies on food environments is needed to strengthen accountability systems to reduce NCDs. The International Network for Food and Obesity/NCDs Research, Monitoring and Action Support (INFORMAS) is a global network of public-interest organizations and researchers that aims to monitor, benchmark and support public and private sector actions to create healthy food environments and reduce obesity, NCDs and their related inequalities. The INFORMAS framework includes two ‘process’ modules, that monitor the policies and actions of the public and private sectors, seven ‘impact’ modules that monitor the key characteristics of food environments and three ‘outcome’ modules that monitor dietary quality, risk factors and NCD morbidity and mortality. Monitoring frameworks and indicators have been developed for 10 modules to provide consistency, but allowing for stepwise approaches (‘minimal’, ‘expanded’, ‘optimal’) to data collection and analysis. INFORMAS data will enable benchmarking of food environments between countries, and monitoring of progress over time within countries. Through monitoring and benchmarking, INFORMAS will strengthen the accountability systems needed to help reduce the burden of obesity, NCDs and their related inequalities.

Monitoring and benchmarking government policies and actions to improve the healthiness of food environments : a proposed Government Healthy Food Environment Policy Index

Government action is essential to increase the healthiness of food environments and reduce obesity, diet-related non-communicable diseases (NCDs), and their related inequalities. This paper proposes a monitoring framework to assess government policies and actions for creating healthy food environments. Recommendations from relevant authoritative organizations and expert advisory groups for reducing obesity and NCDs were examined, and pertinent components were incorporated into a comprehensive framework for monitoring government policies and actions. A Government Healthy Food Environment Policy Index (Food-EPI) was developed, which comprises a ‘policy’ component with seven domains on specific aspects of food environments, and an ‘infrastructure support’ component with seven domains to strengthen systems to prevent obesity and NCDs. These were revised through a week-long consultation process with international experts. Examples of good practice statements are proposed within each domain, and these will evolve into benchmarks established by governments at the forefront of creating and implementing food policies for good health. A rating process is proposed to assess a government's level of policy implementation towards good practice. The Food-EPI will be pre-tested and piloted in countries of varying size and income levels. The benchmarking of government policy implementation has the potential to catalyse greater action to reduce obesity and NCDs.

Monitoring the levels of important nutrients in the food supply

A food supply that delivers energy-dense products with high levels of salt, saturated fats and trans fats, in large portion sizes, is a major cause of non-communicable diseases (NCDs). The highly processed foods produced by large food corporations are primary drivers of increases in consumption of these adverse nutrients. The objective of this paper is to present an approach to monitoring food composition that can both document the extent of the problem and underpin novel actions to address it. The monitoring approach seeks to systematically collect information on high-level contextual factors influencing food composition and assess the energy density, salt, saturated fat, trans fats and portion sizes of highly processed foods for sale in retail outlets (with a focus on supermarkets and quick-service restaurants). Regular surveys of food composition are proposed across geographies and over time using a pragmatic, standardized methodology. Surveys have already been undertaken in several high- and middle-income countries, and the trends have been valuable in informing policy approaches. The purpose of collecting data is not to exhaustively document the composition of all foods in the food supply in each country, but rather to provide information to support governments, industry and communities to develop and enact strategies to curb food-related NCDs.

Monitoring food and non-alcoholic beverage promotions to children

Food and non-alcoholic beverage marketing is recognized as an important factor influencing food choices related to non-communicable diseases. The monitoring of populations' exposure to food and non-alcoholic beverage promotions, and the content of these promotions, is necessary to generate evidence to understand the extent of the problem, and to determine appropriate and effective policy responses. A review of studies measuring the nature and extent of exposure to food promotions was conducted to identify approaches to monitoring food promotions via dominant media platforms. A step-wise approach, comprising ‘minimal’, ‘expanded’ and ‘optimal’ monitoring activities, was designed. This approach can be used to assess the frequency and level of exposure of population groups (especially children) to food promotions, the persuasive power of techniques used in promotional communications (power of promotions) and the nutritional composition of promoted food products. Detailed procedures for data sampling, data collection and data analysis for a range of media types are presented, as well as quantifiable measurement indicators for assessing exposure to and power of food and non-alcoholic beverage promotions. The proposed framework supports the development of a consistent system for monitoring food and non-alcoholic beverage promotions for comparison between countries and over time.

Monitoring the health-related labelling of foods and non-alcoholic beverages in retail settings

Food labelling on food packaging has the potential to have both positive and negative effects on diets. Monitoring different aspects of food labelling would help to identify priority policy options to help people make healthier food choices. A taxonomy of the elements of health-related food labelling is proposed. A systematic review of studies that assessed the nature and extent of health-related food labelling has been conducted to identify approaches to monitoring food labelling. A step-wise approach has been developed for independently assessing the nature and extent of health-related food labelling in different countries and over time. Procedures for sampling the food supply, and collecting and analysing data are proposed, as well as quantifiable measurement indicators and benchmarks for health-related food labelling.

Monitoring foods and beverages provided and sold in public sector settings

This paper outlines a step-wise framework for monitoring foods and beverages provided or sold in publicly funded institutions. The focus is on foods in schools, but the framework can also be applied to foods provided or sold in other publicly funded institutions. Data collection and evaluation within this monitoring framework will consist of two components. In component I, information on existing food or nutrition policies and/or programmes within settings would be compiled. Currently, nutrition standards and voluntary guidelines associated with such policies/programmes vary widely globally. This paper, which provides a comprehensive review of such standards and guidelines, will facilitate institutional learnings for those jurisdictions that have not yet established them or are undergoing review of existing ones. In component II, the quality of foods provided or sold in public sector settings is evaluated relative to existing national or sub-national nutrition standards or voluntary guidelines. Where there are no (or only poor) standards or guidelines available, the nutritional quality of foods can be evaluated relative to standards of a similar jurisdiction or other appropriate standards. Measurement indicators are proposed (within ‘minimal’, ‘expanded’ and ‘optimal’ approaches) that can be used to monitor progress over time in meeting policy objectives, and facilitate comparisons between countries.

Monitoring the impacts of trade agreements on food environments

The liberalization of international trade and foreign direct investment through multilateral, regional and bilateral agreements has had profound implications for the structure and nature of food systems, and therefore, for the availability, nutritional quality, accessibility, price and promotion of foods in different locations. Public health attention has only relatively recently turned to the links between trade and investment agreements, diets and health, and there is currently no systematic monitoring of this area. This paper reviews the available evidence on the links between trade agreements, food environments and diets from an obesity and non-communicable disease (NCD) perspective. Based on the key issues identified through the review, the paper outlines an approach for monitoring the potential impact of trade agreements on food environments and obesity/NCD risks. The proposed monitoring approach encompasses a set of guiding principles, recommended procedures for data collection and analysis, and quantifiable ‘minimal’, ‘expanded’ and ‘optimal’ measurement indicators to be tailored to national priorities, capacity and resources. Formal risk assessment processes of existing and evolving trade and investment agreements, which focus on their impacts on food environments will help inform the development of healthy trade policy, strengthen domestic nutrition and health policy space and ultimately protect population nutrition.

Monitoring and benchmarking population diet quality globally : a step-wise approach

INFORMAS (International Network for Food and Obesity/non-communicable diseases Research, Monitoring and Action Support) aims to monitor and benchmark the healthiness of food environments globally. In order to assess the impact of food environments on population diets, it is necessary to monitor population diet quality between countries and over time. This paper reviews existing data sources suitable for monitoring population diet quality, and assesses their strengths and limitations. A step-wise framework is then proposed for monitoring population diet quality. Food balance sheets (FBaS), household budget and expenditure surveys (HBES) and food intake surveys are all suitable methods for assessing population diet quality. In the proposed ‘minimal’ approach, national trends of food and energy availability can be explored using FBaS. In the ‘expanded’ and ‘optimal’ approaches, the dietary share of ultra-processed products is measured as an indicator of energy-dense, nutrient-poor diets using HBES and food intake surveys, respectively. In addition, it is proposed that pre-defined diet quality indices are used to score diets, and some of those have been designed for application within all three monitoring approaches. However, in order to enhance the value of global efforts to monitor diet quality, data collection methods and diet quality indicators need further development work.