The obesity paradox for mid- and long-term mortality in older cancer patients: a prospective multicenter cohort study.

BACKGROUND: Overweight and obesity are associated with adverse health outcomes. However, substantial literature suggests that they are associated with longer survival among older people. This "obesity paradox" remains controversial. In the context of cancer, the association between overweight/obesity and mortality is complicated by concomitant weight loss (WL). Sex differences in the relation between BMI (in kg/m2) and survival have also been observed. OBJECTIVES: We studied whether a high BMI was associated with better survival, and whether the association differed by sex, in older patients with cancer. METHODS: We studied patients aged ≥70 y from the ELCAPA (Elderly Cancer Patients) prospective open cohort (2007-2016; 10 geriatric oncology clinics, Greater Paris urban area). The endpoints were 12- and 60-mo mortality. We created a variable combining BMI at cancer diagnosis and WL in the previous 6 mo, and considered 4 BMI categories-underweight (BMI < 22.5), normal weight (BMI = 22.5-24.9), overweight (BMI = 25-29.9), and obesity (BMI ≥ 30)-and 3 WL categories-<5% (minimal), 5% to <10% (moderate), and ≥10% (severe). Univariate and multivariate Cox proportional hazards analyses were conducted in men and women. RESULTS: A total of 2071 patients were included (mean age: 81 y; women: 48%; underweight: 30%; normal weight: 23%; overweight: 33%; obesity: 14%; predominant cancer sites: colorectal (18%) and breast (16%); patients with metastases: 49%). By multivariate analysis, obese women with WL < 5% had a lower 60-mo mortality risk than normal-weight women with WL < 5% (adjusted HR: 0.56; 95% CI: 0.37, 0.86; P = 0.012). Overweight/obese women with WL ≥ 5% did not have a lower mortality risk than normal-weight women with WL < 5%. Overweight and obese men did not have a lower mortality risk, irrespective of WL. CONCLUSIONS: By taking account of prediagnosis WL, only older obese women with cancer with minimal WL had a lower mortality risk than their counterparts with normal weight.This trial was registered at clinicaltrials.gov as NCT02884375.

An in vitro diagnostic certified point of care single nucleotide test for IL28B polymorphisms.

Numerous genetic polymorphisms have been identified as associated with disease or treatment outcome, but the routine implementation of genotyping into actionable medical care remains limited. Point-of-care (PoC) technologies enable rapid and real-time treatment decisions, with great potential for extending molecular diagnostic approaches to settings with limited medical infrastructure (e.g., CLIA certified diagnostic laboratories). With respect to resource-limited settings, there is a need for simple devices to implement biomarker guided treatment strategies. One relevant example is chronic hepatitis C infection, for which several treatment options are now approved. Single nucleotide polymorphisms (SNPs) in the IL-28B / IFNL3 locus have been well described to predict both spontaneous clearance and response to interferon based therapies. We utilized the Genedrive® platform to develop an assay for the SNP rs12979860 variants (CC, CT and TT). The assay utilizes a hybrid thermal engine, permitting rapid heating and cooling, enabling an amplification based assay with genetic variants reported using endpoint differential melting cure analysis in less than 60 minutes. We validated this assay using non-invasive buccal swab sampling in a prospective study of 246 chronic HCV patients, achieving 100% sensitivity and 100% specificity (95% exact CI: 98.8-100%)) in 50 minutes as compared to conventional lab based PCR testing. Our results provide proof of concept that precision medicine is feasible in resource-limited settings, offering the first CE-IVD (in vitro diagnostics) validated PoC SNP test. We propose that IL-28B genotyping may be useful for directing patients towards lower cost therapies, and rationing use of costly direct antivirals for use in those individuals showing genetic risk.

Maternal deprivation induces deficits in temporal memory and cognitive flexibility and exaggerates synaptic plasticity in the rat medial prefrontal cortex.

Early life adverse events can lead to structural and functional impairments in the prefrontal cortex (PFC). Here, we investigated whether maternal deprivation (MD) alters PFC-dependent executive functions, neurons and astrocytes number and synaptic plasticity in adult male Long-Evans rats. The deprivation protocol consisted of a daily separation of newborn Long-Evans pups from their mothers and littermates 3h/day postnatal day 1-14. Cognitive performances were assessed in adulthood using the temporal order memory task (TMT) and the attentional set-shifting task (ASST) that principally implicates the PFC and the Morris water maze task (WMT) that does not essentially rely on the PFC. The neurons and astrocytes of the prelimbic (PrL) area of the medial PFC (mPFC) were immunolabelled respectively with anti-NeuN and anti-GFAP antibodies and quantified by stereology. The field potentials evoked by electrical stimulation of ventral hippocampus (ventral HPC) were recorded in vivo in the PrL area. In adulthood, MD produced cognitive deficits in two PFC-dependent tasks, the TMT and ASST, but not in the WMT. In parallel, MD induced in the prelimbic area of the medial PFC an upregulation of long-term potentiation (LTP), without any change in the number of neurons and astrocytes. We provide evidence that MD leads in adults to an alteration of the cognitive abilities dependent on the PFC, and to an exaggerated synaptic plasticity in this region. We suggest that this latter phenomenon may contribute to the impairments in the cognitive tasks.

Maternal deprivation induces depressive-like behaviours only in female rats.

Maternal deprivation (MD) has been developed to study the effects of early adverse experiences on behaviour and neurobiology. It has been proposed to represent a potential animal model of major depression. The purpose of our study was to examine the responses induced by MD in male and female adult Long-Evans rats in tasks designed to explore depressive-like behaviours (forced swimming test (FST), repeated open space swim test (OSST), sucrose solution consumption) and in the novel object recognition and object location tasks. A consistent sexual dimorphism was observed in the responses of male and female rats that underwent MD. In male rats, MD led to increased transitions between behaviours in the FST and increased consumption and preference for sucrose (1%) in comparison with non-deprived rats. In female rats, MD induced a decreased swimming activity on the second day of the OSST and reduced the cognitive performance in an object location task. In both sexes, MD did not alter the swimming activity in the FST and the performance in a novel object recognition task. These divergent responses in male and female rats can be related to the gender differences which exist in depression. However, due to the low amplitude of responses obtained in our study, the MD model in Long-Evans rats does not seem to mimic symptoms of major depression. In contrast, our present results suggest the use of the MD model, especially in females, as a model of the dysthymia, a mild chronic-depressive condition, which has been related to poorer maternal relationship.