Comparison of Body Composition Measurements using a New Caliper, Two Established Calipers, Hydrostatic Weighing, and BodPod

Purposes: (1) To compare the Lafayette Instruments (LI) skinfold caliper to the Lange (L) and Harpenden (H) calipers using a diverse subject population. (2) To determine the validity of the LI caliper in a subset of subjects by comparing body compositions from skinfold thicknesses to those measured by hydrostatic weighing (HW) and air displacement plethysmography (ADP). (3) To compare measurements obtained by experienced (EX) and inexperienced (IX) technicians using all three calipers. Methods: Skinfold measurements were performed by both EX and IX technicians using three different calipers on 21 younger (21.2 ± 1.5 yrs) and 20 older (59.2 ± 4 yrs) subjects. Body compositions were calculated using the Jackson-Pollock seven-site and three-site formulas. HW and ADP tests were performed on a subset of subjects (10 younger, 10 older). Results: No significant differences existed between LI and L or H when measurements were made by EX. Further, the LI-EX measurements were highly correlated to both H-EX and L-EX. No significant differences existed in the subgroup between LI-EX and HW or ADP. Skinfold determinations made by EX and IX were similar. Conclusions: Similar body compositions determined using LI, H, and L suggest that LI determines body composition as effectively as H and L. High correlations between the three calipers support this notion. Similar results between LI and HW/ADP subgroup suggest that the LI caliper may be a valid method of measuring body composition. Overall, performance by IX was similar to EX and suggests similar ease of use for all three calipers

Modeling Human Cancer-induced Cachexia

Talbert et al. developed an inducible mouse model of cachexia caused by pancreatic cancer. This model exhibits features of the human condition, including the progressive depletion of muscle and adipose tissue associated with tumor progression

Linking Symptom Inventories using Semantic Textual Similarity

An extensive library of symptom inventories has been developed over time to measure clinical symptoms, but this variety has led to several long standing issues. Most notably, results drawn from different settings and studies are not comparable, which limits reproducibility. Here, we present an artificial intelligence (AI) approach using semantic textual similarity (STS) to link symptoms and scores across previously incongruous symptom inventories. We tested the ability of four pre-trained STS models to screen thousands of symptom description pairs for related content - a challenging task typically requiring expert panels. Models were tasked to predict symptom severity across four different inventories for 6,607 participants drawn from 16 international data sources. The STS approach achieved 74.8% accuracy across five tasks, outperforming other models tested. This work suggests that incorporating contextual, semantic information can assist expert decision-making processes, yielding gains for both general and disease-specific clinical assessment

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Inflammation as a Therapeutic Target in Cancer Cachexia

Cachexia is a common complication of cancer and is associated with poor quality of life and a decrease in survival. Many patients with cancer cachexia suffer from inflammation associated with elevated cytokines, such as interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF). Single-agent trials to treat cancer cachexia have not led to substantial benefit as the type of cytokine which is elevated has rarely been specified and targeted. Cachexia may also be multifactorial, involving inflammation, anorexia, catabolism, depression, and pain, and targeting the multiple causes will likely be necessary to achieve improvement in weight and appetite. A PUBMED search revealed over 3000 articles on cancer cachexia in the past ten years. We attempted to review any studies related to inflammation and cancer cachexia identified by Google Scholar and PUBMED and further search for articles listed in their references. The National Comprehensive Cancer Network (NCCN) guidelines do not provide any suggestion for managing cancer cachexia except a dietary consult. A more targeted approach to developing therapies for cancer cachexia might lead to more personalized and effective therapy

Prevention of Doxorubicin-Induced Autophagy Attenuates Oxidative Stress and Skeletal Muscle Dysfunction

Clinical use of the chemotherapeutic doxorubicin (DOX) promotes skeletal muscle atrophy and weakness, adversely affecting patient mobility and strength. Although the mechanisms responsible for DOX-induced skeletal muscle dysfunction remain unclear, studies implicate the significant production of reactive oxygen species (ROS) in this pathology. Supraphysiological ROS levels can enhance protein degradation via autophagy, and it is established that DOX upregulates autophagic signaling in skeletal muscle. To determine the precise contribution of accelerated autophagy to DOX-induced skeletal muscle dysfunction, we inhibited autophagy in the soleus via transduction of a dominant negative mutation of the autophagy related 5 (ATG5) protein. Targeted inhibition of autophagy prevented soleus muscle atrophy and contractile dysfunction acutely following DOX administration, which was associated with a reduction in mitochondrial ROS and maintenance of mitochondrial respiratory capacity. These beneficial modifications were potentially the result of enhanced transcription of antioxidant response element-related genes and increased antioxidant capacity. Specifically, our results showed significant upregulation of peroxisome proliferator-activated receptor gamma co-activator 1-alpha, nuclear respiratory factor-1, nuclear factor erythroid-2-related factor-2, nicotinamide-adenine dinucleotide phosphate quinone dehydrogenase-1, and catalase in the soleus with DOX treatment when autophagy was inhibited. These findings establish a significant role of autophagy in the development of oxidative stress and skeletal muscle weakness following DOX administration

Identification of circulating plasma ceramides as a potential sexually dimorphic biomarker of pancreatic cancer‐induced cachexia

Abstract Background Cancer patients who exhibit cachexia lose weight and have low treatment tolerance and poor outcomes compared with cancer patients without weight loss. Despite the clear increased risk for patients, diagnosing cachexia still often relies on self‐reported weight loss. A reliable biomarker to identify patients with cancer cachexia would be a valuable tool to improve clinical decision making and identification of patients at risk of adverse outcomes. Methods Targeted metabolomics, which included panels of amino acids, tricarboxylic acids, fatty acids, acylcarnitines, and sphingolipids, were conducted on plasma samples from patients with confirmed pancreatic ductal adenocarcinoma (PDAC) with and without cachexia and control patients without cancer (n = 10/group, equally divided by sex). Additional patient samples were analysed (total n = 95), and receiver operating characteristic (ROC) analyses were performed to establish if any metabolite could effectively serve as a biomarker of cachexia. Results Targeted profiling revealed that cachectic patients had decreased circulating levels of three sphingolipids compared with either non‐cachectic PDAC patients or patients without cancer. The ratio of C18‐ceramide to C24‐ceramide (C18:C24) outperformed a number of other previously proposed biomarkers of cachexia (area under ROC = 0.810). It was notable that some biomarkers, including C18:C24, were only altered in cachectic males. Conclusions Our findings identify C18:C24 as a potentially new biomarker of PDAC‐induced cachexia that also highlight a previously unappreciated sexual dimorphism in cancer cachexia