The association of nutritional and inflammatory biomarkers with overall survival in patients with non-small-cell lung cancer treated with immune checkpoint inhibitors.

OBJECTIVES: Pretreatment biomarkers are needed to identify patients with non-small-cell lung cancer (NSCLC) likely to have worse survival. This ensures that only patients with a real chance of benefit receive immune checkpoint inhibitor (ICI) treatment. In this study, we examined the associations of baseline nutritional and inflammatory biomarkers with overall survival in a real-world cohort of NSCLC patients who received ICIs. MATERIALS AND METHODS: We used prospectively collected data from the OncoLifeS data biobank. The cohort included 500 advanced-stage NSCLC patients treated with ICIs from May 2015 to June 2021. Biomarkers were evaluated within 2 weeks before ICI treatment: neutrophil-to-lymphocyte ratio, C-reactive protein (CRP), Glasgow prognostic score, CRP/albumin ratio (CAR), prognostic nutritional index (PNI), and advanced lung cancer inflammation index. For each biomarker, low- and high-risk groups were defined using literature-based cut-offs. Adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) were estimated using adjusted survival analysis. RESULTS: Most patients were male (60.8%), the mean baseline age was 65 ± 9 years, and 88% had stage IV disease. For each biomarker, low-risk patients had better overall survival (all, p < 0.001), with CAR and PNI showing the strongest associations. In multivariable analyses a combined CAR/PNI risk score had a stronger association with overall survival (aHR 3.09, 95% CI 2.36-4.06) than CAR alone (aHR 2.22, 95% CI 1.79-2.76) or PNI alone (aHR 2.09, 95% CI 1.66-2.61). CONCLUSION: These results highlight the potential value of nutritional and inflammatory biomarkers, in particular CAR and PNI, in identifying NSCLC patients with highest mortality risk before starting ICI treatment.

Associations between maternal physical activity in early and late pregnancy and offspring birth size: remote federated individual level meta-analysis from eight cohort studies.

OBJECTIVE: Evidence on the impact of leisure time physical activity (LTPA) in pregnancy on birth size is inconsistent. We aimed to examine the association between LTPA during early and late pregnancy and newborn anthropometric outcomes. DESIGN: Individual level meta-analysis, which reduces heterogeneity across studies. SETTING: A consortium of eight population-based studies (seven European and one US) comprising 72 694 participants. METHODS: Generalised linear models with consistent inclusion of confounders (gestational age, sex, parity, maternal age, education, ethnicity, BMI, smoking, and alcohol intake) were used to test associations between self-reported LTPA at either early (8-18 weeks gestation) or late pregnancy (30+ weeks) and the outcomes. Results were pooled using random effects meta-analyses. MAIN OUTCOME MEASURES: Birth weight, large-for-gestational age (LGA), macrosomia, small-for-gestational age (SGA), % body fat, and ponderal index at birth. RESULTS: Late, but not early, gestation maternal moderate to vigorous physical activity (MVPA), vigorous activity, and LTPA energy expenditure were modestly inversely associated with BW, LGA, macrosomia, and ponderal index, without heterogeneity (all: I2  = 0%). For each extra hour/week of MVPA, RR for LGA and macrosomia were 0.97 (95% CI: 0.96, 0.98) and 0.96 (95% CI: 0.94, 0.98), respectively. Associations were only modestly reduced after additional adjustments for maternal BMI and gestational diabetes. No measure of LTPA was associated with risk for SGA. CONCLUSIONS: Physical activity in late, but not early, pregnancy is consistently associated with modestly lower risk of LGA and macrosomia, but not SGA. TWEETABLE ABSTRACT: In an individual participant meta-analysis, late pregnancy moderate to vigorous physical activity modestly reduced birth size outcomes.

Effects of paternal and maternal lifestyle factors on pregnancy complications and perinatal outcome. A population-based birth-cohort study: the GECKO Drenthe cohort.

STUDY QUESTION: Do paternal and maternal lifestyle factors influence the risk of hypertensive pregnancy complications, gestational diabetes mellitus (GDM), spontaneous preterm birth and small-for-gestational-age (SGA)? SUMMARY ANSWER: Paternal lifestyle factors do not exert an independent effect on the investigated outcomes while maternal prepregnancy BMI and maternal smoking during pregnancy influence the risk of hypertensive pregnancy complications, GDM and SGA. WHAT IS KNOWN ALREADY: Maternal lifestyle factors are associated with perinatal complications, but the impact of paternal lifestyle factors is unclear. STUDY DESIGN, SIZE, DURATION: Data from the GECKO (Groningen Expert Center for Kids with Obesity) Drenthe cohort, a prospective population-based birth-cohort of children born between April 2006 and April 2007 in a northern province of The Netherlands, were analysed. The parents of 2958 children (62% of those approached) gave their consent to participate in the study and the data of 2264 (77%) couples were available for analysis. PARTICIPANTS/MATERIALS, SETTINGS, METHOD: All pregnant women in the Dutch province of Drenthe with an expected date of delivery between April 2006 and April 2007 were invited to participate and included during the third trimester of their pregnancy or within 6 months after delivery. All consenting couples received extensive questionnaires including lifestyle, biological and socio-demographic-related questions covering the period of 6 months prior to conception. Outcome data were obtained from midwives and hospital registries. Univariable and multivariable logistic regression analyses were used to determine the impact of the lifestyle factors on the primary outcome measures. MAIN RESULTS AND THE ROLE OF CHANCE: Of all 2264 women, 241 women (10.6%) developed a hypertensive pregnancy complication, 50 women (2.2%) developed GDM, 79 (3.5%) children were spontaneously delivered preterm and 155 children (6.8%) were SGA. All paternal and maternal lifestyle factors were positively correlated. Multivariable analysis showed that paternal lifestyle factors did not have an independent influence on the investigated outcomes. Of the maternal factors, prepregnancy BMI was independently associated with an increased risk of a hypertensive disorder during pregnancy (odds ratio (OR): 1.12, 95% CI 1.09-1.16), a higher risk of GDM (OR BMI >23 kg/m(2), per BMI unit: 1.13, 95% CI 1.08-1.18) and with a decreased risk of SGA (OR per BMI point 0.94, 95% CI 0.90-0.99). Maternal smoking during pregnancy was significantly associated with SGA (OR 3.00, 95% CI 1.80-4.99) in multivariable analysis. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the questionnaire may have induced recall bias. Selection bias might have occurred, as ethnic minorities were less willing to co-operate in the GECKO Drenthe study. The possibility of misclassification bias regarding the primary outcome measures cannot be ruled out. Inclusion bias might have occurred as not all questionnaires of the parents of the children participating in the GECKO Drenthe cohort were completed. WIDER IMPLICATIONS OF THE FINDINGS: Paternal lifestyle factors do not have an independent effect on the investigated adverse pregnancy outcomes. However, as paternal and maternal lifestyles are positively correlated, both partners should be involved in preconception counselling regarding the investigated outcome measures.

Prevention of the metabolic syndrome in IGT subjects in a lifestyle intervention: results from the SLIM study.

BACKGROUND AND AIMS: The Study on Lifestyle intervention and Impaired glucose tolerance Maastricht (SLIM), a randomized controlled trial, directed at diet and physical activity in impaired glucose tolerant subjects was effective to improve glucose tolerance and prevent type 2 diabetes. The aim of this study was to determine the effects of the SLIM lifestyle intervention on the incidence and prevalence of the metabolic syndrome (MetS) during the active intervention and four years thereafter. METHODS AND RESULTS: MetS was diagnosed according to the NCEP ATP III criteria. At baseline, 66.4% of all participants (n = 146, age 57 ± 7 years, BMI 29.7 ± 3.6, 51.3% female) fulfilled the criteria for MetS. No significant difference in MetS prevalence was observed between the intervention (63.9%) and control group (68.9%). At the end of active intervention (average duration 4.2 ± 2.0 years), prevalence of MetS was significantly lower in the intervention group (52.6%, n = 57) compared to the control group (74.6%, n = 59) (p = 0.014). Furthermore, in participants without MetS at baseline, cumulative incidence of MetS was 18.2% in the intervention group at the end of active intervention, compared to 73.7% in the control group (Log-rank test, p = 0.011). Four years after stopping active intervention, the reduced incidence of MetS was maintained (Log-rank test, p = 0.002). CONCLUSION: In conclusion, a combined diet-and-exercise intervention to improve glucose tolerance, not only prevented type 2 diabetes, but also reduced the prevalence of MetS and prevented MetS development, showing the long-term impact of lifestyle intervention on cardiovascular risk reduction.

Predictors of lifestyle intervention outcome and dropout: the SLIM study.

BACKGROUND/OBJECTIVES: To evaluate the effect of a 4.1-year (range 3-6 years) lifestyle intervention according to general public health recommendations on glucose tolerance and dropout in a Dutch population with impaired glucose tolerance (IGT). SUBJECTS/METHODS: In the Study on Lifestyle intervention and Impaired glucose tolerance Maastricht, 147 Caucasian IGT subjects were randomized to an intervention group (INT: n=74; 38 male, 36 female) and control group (CON: n=73; 37 male, 36 female). Annually, subjects underwent measurements of body weight, anthropometry, glucose tolerance (oral glucose tolerance test), insulin resistance (homeostasis model assessment-insulin resistance), maximal aerobic capacity (VO(2) max), blood lipids and blood pressure. INT received individual advice regarding a healthy diet and physical activity. RESULTS: INT decreased their saturated fat intake, increased their carbohydrate intake (P<0.05) and VO(2) max (P=0.04) compared with CON. Body weight did not change significantly (P=0.20) between the groups. After an initial decrease, 2-h glucose levels overall increased in INT (+0.11 mmol/l), but significantly less than CON (+1.18 mmol/l; P=0.04). Diabetes incidence was lower in INT versus CON (30 versus 56%, P=0.04). Change in body weight was associated with change in 2-h glucose levels (ß=0.399 mmol/l per kg, P=0.02). Dropouts had a lower aerobic fitness and socioeconomic status, and a higher body mass index (BMI) and 2-h glucose compared with non-dropouts. CONCLUSIONS: Prolonged feasible changes in diet and physical activity prevent deterioration of glucose tolerance and reduce diabetes risk. Low socioeconomic status, low aerobic fitness and high BMI and 2-h glucose are indicative of dropout to the program.

Maternal and paternal transmission of type 2 diabetes: influence of diet, lifestyle and adiposity.

OBJECTIVE: Transmission of family history of type 2 diabetes to the next generation is stronger for maternal than paternal diabetes in some populations. The aim of the present study was to investigate whether this difference is explained by diet, lifestyle factors and/or adiposity. METHODS: We analysed 35174 participants from the Dutch contribution to the European Prospective Investigation into Cancer and Nutrition, a prospective population-based cohort (aged 20-70 years) with a median follow-up of 10.2 years. Parental history of diabetes was self-reported. Occurrence of diabetes was mainly identified by self-report and verified by medical records. RESULTS: Amongst 35174 participants, 799 incident cases of diabetes were observed. In age- and sex-adjusted analyses, hazard ratio (HR) and 95% confidence intervals (CIs) for diabetes by maternal and paternal diabetes were 2.66 (2.26-3.14) and 2.40 (1.91-3.02), respectively. Maternal transmission of risk of diabetes was explained by diet (9.4%), lifestyle factors including smoking, alcohol consumption, physical activity and educational level (7.8%) and by adiposity, i.e. body mass index and waist and hip circumference (23.5%). For paternal transmission, the corresponding values were 2.9%, 0.0% and 9.6%. After adjustment for diet, lifestyle factors and adiposity, the HRs for maternal (2.20; 95% CI, 1.87-2.60) and paternal (2.23; 95% CI, 1.77-2.80) transmission of diabetes were comparable. CONCLUSIONS: Both maternal and paternal diabetes are associated with increased risk of type 2 diabetes, independently of diet, lifestyle and adiposity. The slightly higher risk conferred by maternal compared to paternal diabetes was explained by a larger contribution of diet, lifestyle factors and adiposity.

Metabolic flexibility in the development of insulin resistance and type 2 diabetes: effects of lifestyle.

Lipotoxicity in skeletal muscle plays a critical role in the aetiology of insulin resistance and type 2 diabetes mellitus by interference of lipid metabolites with insulin signalling and action. The dynamics of lipid oxidation and fine tuning with fatty acid uptake and intramyocellular triacylglycerol turnover may be very important to limit the accumulation of lipid intermediates. The use of metabolic inflexibility, defined as the impaired capacity to increase fat oxidation upon increased fatty acid availability and to switch between fat and glucose as the primary fuel source after a meal, does more justice to the complexity of changes in fuel oxidation during the day. Fatty acid availability, uptake and oxidation all play a role in metabolic flexibility and insulin resistance. During high fatty acid availability, fatty acid transporters may limit cellular and mitochondrial fatty acid uptake and thus limit fat oxidation. After a meal, when the demand for fatty acids as fuel is low, an increased fractional extraction of lipids from plasma may promote intramyocellular lipid accumulation and insulin resistance. Furthermore, defects in fuel switching cluster together with impaired mitochondrial content and/or function. Lifestyle changes in dietary fat intake, physical activity and weight loss may improve metabolic flexibility in skeletal muscle, and thereby contribute to the prevention of type 2 diabetes.

Improvements in glucose tolerance and insulin sensitivity after lifestyle intervention are related to changes in serum fatty acid profile and desaturase activities: the SLIM study.

AIMS/HYPOTHESIS: The aim of this study was to investigate whether lifestyle intervention-induced changes in serum fatty acid profile of cholesteryl esters and estimated desaturase activities are related to improvements in insulin sensitivity in subjects at risk of type 2 diabetes. MATERIALS AND METHODS: In the Study on Lifestyle Intervention and Impaired Glucose Tolerance Maastricht (SLIM), 97 men and women with IGT were randomised to a combined diet and exercise programme (47 intervention) or a control group (50 control subjects). At baseline and after 1 year the following assessments were made: an OGTT, an exercise test to determine maximal aerobic capacity, anthropometry, and analysis of the serum fatty acid profile of cholesteryl esters. RESULTS: The lifestyle programme was effective in reducing the intake of total and saturated fat, increasing physical activity, reducing obesity and improving insulin sensitivity and glucose tolerance. Regression analysis of the total population showed that an increase in the C20:4 n-6/C20:3 n-6 ratio (estimated Delta5-desaturase activity) and reductions in the C18:3 n-6/C18:2 n-6 ratio (estimated Delta6-desaturase activity) and the C16:1 n-7/C16:0 ratio (estimated Delta9-desaturase activity or stearoyl-CoA desaturase-1) were significantly associated with a decrease in homeostasis model assessment for insulin resistance. After adjustment for lifestyle changes (change in percentage body fat, aerobic capacity and saturated fat intake), these associations were partly reduced, but remained statistically significant. CONCLUSIONS/INTERPRETATION: Lifestyle-induced changes in fatty acid profile of cholesteryl esters and desaturase activities were independently related to changes in insulin sensitivity in subjects at risk of type 2 diabetes.