Search

IMPORTANCE Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma. OBJECTIVE To determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor. DESIGN, SETTING, AND PARTICIPANTS Thiswas a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months' follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023. INTERVENTION Patients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8mg/m2) or placebo. All patients received intravenous pemetrexed (500mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months. MAIN OUTCOMES AND MEASURES The primary end pointwas overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only. RESULTS Among 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95%CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95%CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95%CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (

Previous research and experience points to many advantages if sheet metal forming is simulated with elastic dies. Some areas that are enabled by simulations with elastic dies are virtual spotting, improved digital twins, and improved production support. A promising method was selected from the literature, and after important modifications it is deemed to be fast and robust for simulating industrial sized dies. The method consists of meshing die solids with a coarse mesh to represent the structural behaviour of the die. The forming surfaces are then represented by a fine shell mesh connected to the solid mesh by tied contacts with an offset. With additional modifications to reduce solver time this yields a robust and flexible way of modelling sheet metal forming with elastic dies. There is an increase in preprocessing and simulation time compared to using rigid tools, but industrial dies can now be modeled within an hour and solved within a working day. It is also easy to update the model by replacing separate parts such as die solids or forming surfaces. One of the main criteria in favor of the selected approach is the realistic modeling of blankholder and cushion systems. In this paper simulations of three industrial cases are demonstrated: one case of virtual die spotting and two cases of production support. The three cases demonstrate the importance and potential of using elastic dies during virtual die tryout, production support, and for cases like digital twins and production control., Eureka Smart Camber

Sheet metal forming (SMF) simulations are traditionally carried out with rigid active forming surfaces. This means that the elasticity and dynamics of presses and die structures are ignored. The only geometries of the tools included in the simulations are the active forming surfaces. One reason for this simplification is the large amount of computational power that is required to solve finite element (FE) models that incorporates elastic stamping dies. Another reason is the lack of die CAD models before the later stages of stamping projects. Research during the last couple of decades indicated potential large benefits when including elastic dies in SMF simulations. For example, for simulating die try-out or for Digital Twins of presses and dies. Even though the need and potential benefits of elastic dies in simulations are well known it is not yet implemented on a wide scale. The main obstacles have been lacking data on presses and dies, long simulation times, and no standardized implementation in SMF software. This paper presents an overview of existing methods for SMF simulations with elastic dies and discuss their respective benefits and drawbacks. The survey of methods shows that simulation models with elastic tools will be needed for detailed analyses of forming operations and also for purposes like digital twins. On the other hand, simplified and robust models can be developed for non-FEA users to carry out simple one-step compensation of tool surfaces for virtual spotting purposes. The most promising and versatile method from the literature is selected, modified, and demonstrated for industrial sized dies., Eureka Smart Camber

Background and aims: In previous studies on environmental contaminants and diabetes only a limited number of contaminants have been evaluated. The aim with the present study is therefore to obtain a comprehensive picture of the relationships between a large number of environmental contaminants and prevalent diabetes. Materials and methods: In 10 examination cycles in The National Health and Nutrition Examination Survey (NHANES) (1999-2017) altogether 116 different environmental contaminants were evaluated in the circulation or urine in relation to prevalent diabetes. Similar analyses were also performed in the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS) study (n=1016, all aged 70 years, 50% women, 42 contaminants). The logistic regression models were adjusted for age, sex, race, education, BMI, alcohol intake, smoking and lipids. Results: In a meta-analysis of the 10 NHANES examinations, thirty-six contaminants were significantly related to prevalent diabetes. Those contaminants represent a number of different classes, such as metals, PCBs, dioxins, furans, pesticides, PFAS, phthalates, and phenols. Some of these relationships were inverse, such as lead, cadmium, mercury, barium, cesium and strontium, some PFAS and furans, as well as benzo-phenone-3. In the smaller PIVUS study (119 prevalent diabetes cases), significant relationships similar to NHANES were seen for some PCBs, p,p´-DDE and lead. PFHxS and PFOA, showed inverse relationships also in PIVUS. The same was seen for mercury and cadmium. Conclusion: Many environmental contaminants were related to diabetes in the NHANES study. Some of these relationships, mainly some metals and PFAS, were negative. Many of these results were similar in the smaller PIVUS study. These findings need be evaluated in prospective studies.

Background and aim: In previous studies on environmental contaminants and diabetes only a limited number of contaminants have been evaluated. The aim with the present study is therefore to obtain a comprehensive picture of the relationships between a large number of environmental contaminants and prevalent diabetes. Methods: In 10 examination cycles in The National Health and Nutrition Examination Survey (NHANES) (1999–2017) altogether 116 different environmental contaminants were evaluated in the circulation or urine in relation to prevalent diabetes. Similar analyses were also performed in the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS) study (n=1016, all aged 70 years, 50% women, 42 contaminants). The logistic regression models were adjusted for age, sex, race, education, BMI, alcohol intake, smoking and lipids. Results: In a meta-analysis of the 10 NHANES examinations, thirty-six contaminants were significantly related to prevalent diabetes. Those contaminants represent a number of different classes, such as metals, PCBs, dioxins, furans, pesticides, PFAS, phthalates, and phenols. Some of these relationships were inverse, such as lead, cadmium, mercury, barium, cesium and strontium, some PFAS and furans, as well as benzophenone-3. In the smaller PIVUS study (119 prevalent diabetes cases), significant relationships similar to NHANES were seen for some PCBs, p,p’-DDE and lead. PFHxS and PFOA, showed inverse relationships also in PIVUS. The same was seen for mercury and cadmium. Conclusions: Many environmental contaminants were related to diabetes in the NHANES study. Some of these relationships, mainly some metals and PFAS, were negative. Many of these results were similar in the smaller PIVUS study. These findings need be evaluated in prospective studies.

Anorexia is experienced by most people with lung cancer during the course of their disease and treatment. Anorexia reduces response to chemotherapy and the ability of patients to cope with, and complete their treatment leading to greater morbidity, poorer prognosis and outcomes. Despite the significant importance of cancer-related anorexia, current therapies are limited, have marginal benefits and unwarranted side effects. In this multi-site, randomised, double blind, placebo controlled, phase II trial, participants will be randomly assigned (1:1) to receive once-daily oral dosing of 100mg of anamorelin HCl or matched placebo for 12 weeks. Participants can then opt into an extension phase to receive blinded intervention for another 12 weeks (weeks 13-24) at the same dose and frequency. Adults (≥18 years) with small cell lung cancer (SCLC); newly diagnosed with planned systemic therapy OR with first recurrence of disease following a documented disease-free interval ≥6 months, AND with anorexia (i.e., ≤ 37 points on the 12-item Functional Assessment of Anorexia Cachexia Treatment (FAACT A/CS) scale) will be invited to participate. Primary outcomes are safety, desirability and feasibility outcomes related to participant recruitment, adherence to interventions, and completion of study tools to inform the design of a robust Phase III effectiveness trial. Secondary outcomes are the effects of study interventions on body weight and composition, functional status, nutritional intake, biochemistry, fatigue, harms, survival and quality of life. Primary and secondary efficacy analysis will be conducted at 12 weeks. Additional exploratory efficacy and safety analyses will also be conducted at 24 weeks to collect data over longer treatment duration. The feasibility of economic evaluations in Phase III trial will be assessed, including the indicative costs and benefits of anamorelin for SCLC to the healthcare system and society, the choice of methods for data collection and the f

BACKGROUND: Lung cancer is the leading cause of cancer-related death globally. Physical activity and exercise provide unequivocal benefits to those living with and beyond lung cancer. However, few of those living with and beyond cancer meet the national physical activity guidelines. Various barriers exist for this population's engagement in physical activity and exercise, such as the lack of knowledge and lack of tailored information, little access to exercise specialists, fatigue, and mobility challenges. Digitally delivered programmes have the potential to address several of these barriers, with techniques like "computer-tailoring" available to enable the delivery of tailored content at a time and place that is convenient. However, evaluation of such programmes is needed prior to implementation. This protocol describes a single group study that will examine the feasibility and acceptability of an online tool (ExerciseGuide UK) that provides those living with and beyond lung cancer web-based computer-tailored physical activity prescription and modules underpinned by behaviour change theories. METHODS: Thirty-five individuals diagnosed with lung cancer, or cancer affecting the lung (e.g. pleural mesothelioma), will be recruited into a single-intervention arm. The platform will provide tailored resources and a personalised physical activity programme using IF-THEN algorithms. Exercise prescription will be tailored on factors such as self-reported specific pain location, exercise history, and current physical fitness. In addition, modules grounded in behaviour change will supplement the physical activity programme and will focus on topics such as exercise benefits, safety, goal setting, and tracking. The primary outcome will be assessed using pre-established criteria on feasibility and mixed-methods approach for acceptability. Secondary outcomes will explore changes in the physical activity, quality of life, anxiety, and depression. DISCUSSION: This manuscript describ

Background Microvascular complications are common in people with diabetes, where poor glycaemic control is the major contributor. The aim of this study was to explore the association between elevated LDL cholesterol levels and the risk of retinopathy or nephropathy in young individuals with type 1 diabetes. Methods This was a nationwide observational population-based cohort study, including all children and adults with a duration of type 1 diabetes of <= 10 years, identified in the Swedish National Diabetes Register between 1998 and 2017. We calculated the crude incidence rates with 95% confidence intervals (CIs) and used multivariable Cox regression to estimate crude and adjusted hazard ratios (HRs) of retinopathy or nephropathy in four LDL cholesterol categories: <2.6 (Reference), 2.6-3.4, 3.4-4.1 and > 4.1 mmol L-1. Results In total, 11 024/12 350 (retinopathy/nephropathy, both cohorts, respectively) children and adults (median age 21 years, female 42%) were followed up to 28 years from diagnosis until end of study. Median duration of diabetes when entering the study was 6 and 7 years in the retinopathy and nephropathy cohort, respectively. Median LDL cholesterol was 2.4 mmol L-1, and median HbA1c level was 61 mmol mol(-1) (7.7 %). After multivariable adjustment, the HRs (95% CI) for retinopathy in individuals with LDL cholesterol levels of 2.6-3.4, 3.4-4.1 or > 4.1 mmol L-1 were as follows: 1.13 (1.03-1.23), 1.16 (1.02-1.32) and 1.18 (0.99-1.41), compared with the reference. The corresponding numbers for nephropathy were as follows: 1.15 (0.96-1.32), 1.30 (1.03-1.65) and 1.41 (1.06-1.89). Conclusions Young individuals with type 1 diabetes exposed to high LDL cholesterol levels have an increased risk of retinopathy and nephropathy independent of glycaemia and other identified risk factors for vascular complications., Funding Agencies|Swedish Heart-Lung FoundationSwedish Heart-Lung Foundation [20190298]; Stockholm County CouncilStockholm County Council [20170120]; Karolinska InstituteKarolinska Institutet [20170120]; Stockholm City Council; Barndiabetesfonden; Diabetesfonden