Assessment of body composition in breast cancer patients: concordance between transverse computed tomography analysis at the fourth thoracic and third lumbar vertebrae.

Introduction: Specific body composition markers derived from L3 axial computed tomography (CT) images predict clinical cancer outcomes, including chemotherapy toxicity and survival. However, this method is only applicable to those undergoing lumbar (L3) CT scanning, which is not universally conducted in early breast cancer cases. This study aimed to evaluate CT analysis at T4 as a feasible alternative marker of body composition in breast cancer. Method: All patients participated in the Investigating Outcomes from Breast Cancer: Correlating Genetic, Immunological, and Nutritional (BeGIN) Predictors observational cohort study (REC reference number: 14/EE/1297). Staging chest-abdomen-pelvic CT scan images from 24 women diagnosed with early breast cancer at University Hospital Southampton were analysed. Adipose tissue, skeletal muscle, and muscle attenuation were measured from the transverse CT slices' cross-sectional area (CSA) at T4 and L3. Adipose tissue and skeletal muscle area measurements were adjusted for height. Spearman's rank correlation coefficient analysis was used to determine concordance between body composition measurements using CT analysis at L3 and T4 regions. Results: Derived estimates for total adipose tissue, subcutaneous adipose tissue, and intramuscular adipose tissue mass following adjustment for height were highly concordant when determined from CSAs of CT slices at T4 and L3 (Rs = 0.821, p < 0.001; Rs = 0.816, p < 0.001; and Rs = 0.830, p < 0.001). In this cohort, visceral adipose tissue (VAT) and skeletal muscle estimates following height adjustment were less concordant when measured by CT at T4 and L3 (Rs = 0.477, p = 0.039 and Rs = 0.578, p = 0.003). The assessment of muscle attenuation was also highly concordant when measured by CT at T4 and L3 (Rs = 0.840, p < 0.001). Discussion: These results suggest that the CT analysis at T4 and L3 provides highly concordant markers for total adipose, subcutaneous adipose, and intramuscular adipose estimation, but not VAT, in this breast cancer population. High concordance between T4 and L3 was also found when assessing skeletal muscle attenuation. Lower concordance was observed for the estimates of skeletal muscle area, potentially explained by differences in the quantity and proportions of axial and appendicular muscle between the thorax and abdomen. Future studies will determine the value of T4 metrics as predictive tools for clinical outcomes in breast cancer.

Body composition and chemotherapy toxicity in women with early breast cancer (CANDO-3): protocol for an observational cohort study.

INTRODUCTION: Systemic anticancer therapy is given to selected patients with early breast cancer (EBC) before or after surgery with the aim of eradicating micrometastatic spread and reducing the risk of cancer recurrence. Chemotherapy treatment is most effective when patients receive the optimum dose, on time and without delays or reductions in their treatment doses. Most chemotherapy drugs are dosed according to body surface area calculated from a patient's height and weight. These calculations were however designed based on data from normal weight patients. This has resulted in uncertainty as to the optimal dosing for patients with different amounts of blood, muscle and fatty tissue (body composition). This study uses segmental bioelectrical impedance analysis (using the Seca mBCA 515) to determine whether differences in the measures of resistance and reactance, and derived estimates of body composition, are predictive of chemotherapy toxicity in the treatment of EBC. METHODS AND ANALYSIS: A prospective observational cohort study of women with EBC in whom adjuvant or neoadjuvant chemotherapy is planned. A total of 300 participants will be recruited across nine UK hospital sites. The primary outcome is to determine if higher fat mass index is associated with increased National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 grade 3 (or higher) chemotherapy toxicity. ETHICS AND DISSEMINATION: This study has received ethical approval from the South Central Hampshire B Research Ethics Committee, England (19/SC/0596: IRAS: 263666). The chief investigator and coinvestigators will be responsible for publication of the study findings in a peer-reviewed journal, on behalf of all collaborators. TRIAL REGISTRATION NUMBER: ISRCTN79577461.

Quality control issues related to assessment of body composition.

There are no internationally agreed quality standards for the measurement of stature, weight, and body composition. This lack of agreement constrains the quality of work in nutrition and must be addressed in order to build systemic capacity within the Scaling Up Nutrition agenda. There is a need to reach agreement and define standards of performance and the required training to be able to demonstrate the competency of those responsible for making the measurements. This, together with the adoption of standardized protocols, traceable reference materials, quality assurance frameworks, and publication guidance, would mark an important first step in improving the conduct and interpretation of measurements of growth and body composition.

Proteome-wide analyses of human hepatocytes during differentiation and dedifferentiation.

UNLABELLED: Failure to predict hepatotoxic drugs in preclinical testing makes it imperative to develop better liver models with a stable phenotype in culture. Stem cell-derived models offer promise, with differentiated hepatocyte-like cells currently considered to be "fetal-like" in their maturity. However, this judgment is based on limited biomarkers or transcripts and lacks the required proteomic datasets that directly compare fetal and adult hepatocytes. Here, we quantitatively compare the proteomes of human fetal liver, adult hepatocytes, and the HepG2 cell line. In addition, we investigate the proteome changes in human fetal and adult hepatocytes when cultured in a new air-liquid interface format compared to conventional submerged extracellular matrix sandwich culture. From albumin and urea secretion, and luciferase-based cytochrome P450 activity, adult hepatocytes were viable in either culture model over 2 weeks. The function of fetal cells was better maintained in the air-liquid interface system. Strikingly, the proteome was qualitatively similar across all samples but hierarchical clustering showed that each sample type had a distinct quantitative profile. HepG2 cells more closely resembled fetal than adult hepatocytes. Furthermore, clustering showed that primary adult hepatocytes cultured at the air-liquid interface retained a proteome that more closely mimicked their fresh counterparts than conventional culture, which acquired myofibroblast features. Principal component analysis extended these findings and identified a simple set of proteins, including cytochrome P450 2A6, glutathione S transferase P, and alcohol dehydrogenases as specialized indicators of hepatocyte differentiation. CONCLUSION: Our quantitative datasets are the first that directly compare multiple human liver cells, define a model for enhanced maintenance of the hepatocyte proteome in culture, and provide a new protein "toolkit" for determining human hepatocyte maturity in cultured cells.

Chemokine receptor 4 plays a key role in T cell recruitment into the airways of asthmatic patients.

T lymphocytes of the Th2 type are central orchestrators of airway inflammation in asthma. The mechanisms that regulate their accumulation in the asthmatic airways remains poorly understood. We tested the hypothesis that CCR4, preferentially expressed on T lymphocytes of the Th2 type, plays a critical role in this process. We enumerated by flow cytometry the CCR4-expressing T cells from blood, induced sputum, and biopsy samples of patients with asthma and control subjects. We showed a positive correlation between the numbers of peripheral blood CCR4+ T cells and asthma severity, provided evidence of preferential accumulation of CCR4+ T cells in asthmatic airways, and demonstrated that CCR4+ but not CCR4- cells from patients with asthma produce Th2 cytokines. Explanted airway mucosal biopsy specimens, acquired by bronchoscopy from subjects with asthma, were challenged with allergen and the explant supernatants assayed for T cell chemotactic activity. Allergen-induced ex vivo production of the CCR4 ligand, CCL17 was raised in explants from patients with asthma when compared with healthy controls. Using chemotaxis assays, we showed that the T cell chemotactic activity generated by bronchial explants can be blocked with a selective CCR4 antagonist or by depleting CCR4+ cells from responder cells. These results provide evidence that CCR4 might play a role in allergen-driven Th2 cell accumulation in asthmatic airways. Targeting this chemokine receptor in patients with asthma might reduce Th2 cell-driven airway inflammation; therefore, CCR4 antagonists could be an effective new therapy for asthma. This study also provides wider proof of concept for using tissue explants to study immunomodulatory drugs for asthma.

Neuropeptide alpha-MSH exerts pro-inflammatory effects on Neisseria meningitidis infection in vitro.

OBJECTIVE AND DESIGN: alpha-Melanoycte stimulating hormone (alpha-MSH), a neuropeptide hormone with reported anti-microbial and immuno-modulatory properties in vitro, has previously been detected in the cerebrospinal fluid of children with bacterial meningitis. We investigated the therapeutic effects of alpha-MSH administration on Neisseria meningitidis infection of human meningeal cell cultures in vitro. MATERIALS AND METHODS: Meningeal cell lines (n = 2) were infected with meningococci (10(2)-10(8) cfu/monolayer), isolated bacterial outer membranes (OM; 1 microg/ml) or lipo-oligosaccharide (LOS; 1 microg/ml) with and without alpha-MSH (10(-5)-10 microM). Bacterial adherence was quantified at 6 h, and cytokine production and microbicidal activity of alpha-MSH for meningococci were assessed at 24 h. RESULTS: Compared with infection by meningococci alone, alpha-MSH (10 microM) up-regulated secretion of IL-6 and IL-8 (mean values increased from approximately 33 to 60 ng/ml), RANTES (mean values increased from approximately 26 to 105 ng/ml) and GM-CSF (mean values increased from approximately 0.3 to 1 ng/ml; P < 0.05). Upregulated secretion correlated with a neuropeptide-mediated rapid and >5-fold increase (P < 0.05) in bacterial adherence to cells and was dependent on OM components including LOS acting synergistically with alpha-MSH. Meningococci were resistant to the anti-microbial activity of alpha-MSH at all concentrations tested. CONCLUSIONS: Our study demonstrates that a potentially therapeutic neuropeptide exerts pro-inflammatory effects during meningococcal infection in vitro and its use in the treatment of meningitis is contra-indicated.