Primary Tumor Fluorine-18 Fluorodeoxydglucose (18F-FDG) Is Associated With Cancer-Associated Weight Loss in Non-Small Cell Lung Cancer (NSCLC) and Portends Worse Survival.

Aim: To investigate the diagnostic potential of and associations between tumor 18F-FDG uptake on PET imaging and cancer-associated weight loss. Methods: 774 non-small cell lung cancer (NSCLC) patients with pre-treatment PET evaluated between 2006 and 2014 were identified. Using the international validated definition of cachexia, the presence of clinically significant pretreatment cancer-associated weight loss (WL) was retrospectively determined. Maximum Standardized Uptake Value (SUVMax) of 18F-FDG was recorded and dichotomized based on 3 experimental cutpoints for survival analyses. Each SUVMax cutpoint prioritized either survival differences, total cohort comparison sample sizes, or sample size by stage. Patient outcomes and associations between SUVMax and cancer-associated weight loss were assessed by multivariate, categorical, and survival analyses. Results: Patients were found to have an increased likelihood of having WL at diagnosis associated with increasing primary tumor SUVMax after controlling for potentially confounding patient and tumor characteristics on multivariate logistic regression (OR 1.038; 95% CI: 1.012, 1.064; P=0.0037). After stratifying the cohort by WL and dichotomized SUVMax, both factors were found to be relevant in predicting survival outcomes when the alternative variable was constant. Of note, the most striking survival differences contributed by WL status occurred in high SUVMax groups, where the presence of WL predicted a median survival time detriment of up to 10 months, significant regardless of cutpoint determination method applied to categorize high SUVMax patients. SUVMax classification was found to be most consistently relevant in both WL and no WL groups. Conclusions: The significant positive association between significant pretreatment cancer-associated weight loss and primary tumor SUVMax underscores increased glucose uptake as a component of catabolic tumor phenotypes. This substantiates 18F-FDG PET analysis as a prospective tool for assessment of cancer-associated weight loss and corresponding survival outcomes. Furthermore, the survival differences observed between WL groups across multiple SUVMax classifications supports the importance of weight loss monitoring in oncologic workups. Weight loss in the setting of NSCLCs with higher metabolic activity as determined by 18F-FDG PET signal should encourage more aggressive and earlier palliative care interventions.

Associations of Prior Chronic Use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Glucocorticoids With Cachexia Incidence and Survival.

Background: Cachexia is an inflammatory and metabolic syndrome of unintentional weight loss through depletion of muscle and adipose tissue. There is limited knowledge of how chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids affect cachexia development. The purpose of this study was to investigate associations between prior long-term use of NSAIDs or glucocorticoids with cachexia incidence and post-diagnosis weight loss progression in a retrospective cancer patient cohort. Methods: Of 3,802 lung or gastrointestinal cancer patient records, 3,180 comprised our final cohort. Patient demographic information, tumor qualities, medication histories, and comorbidities were assessed. Cachexia was defined as having developed prior to oncologic treatment. Statistical evaluations included categorical, multivariate logistic regression, and log-rank survival analyses. Development of substantial post-diagnosis weight loss was calculated and interpreted for patients without cachexia at diagnosis. Results: Chronic prior use of any NSAID or glucocorticoid medication was associated with approximate absolute and relative reductions in cachexia incidence at diagnosis of 10 and 25 percent (P<0.0001). In multivariate analyses, NSAID medications demonstrated a 23 percent reduction in cachexia incidence likelihood (OR=0.770; 95% CI=0.594, 0.998; P=0.0481). Patients without cachexia at diagnosis were significantly more likely to develop substantial post-diagnosis weight loss from pre-diagnosis use groups of glucocorticoids (OR= 1.452; 95% CI=1.065, 1.979; P=0.0183) or NSAIDs (OR=1.411; 95% CI=1.082, 1.840; P=0.011). Conclusions: Our findings suggest a protective effect of prior anti-inflammatory medications, primarily NSAIDs, against manifestations of the cachexia phenotype at cancer diagnosis. These observations support further exploration of potential therapeutic benefits from anti-inflammatory medications early in cancer management.

An in vitro tumorigenesis model based on live-cell-generated oxygen and nutrient gradients.

The tumor microenvironment (TME) is multi-cellular, spatially heterogenous, and contains cell-generated gradients of soluble molecules. Current cell-based model systems lack this complexity or are difficult to interrogate microscopically. We present a 2D live-cell chamber that approximates the TME and demonstrate that breast cancer cells and macrophages generate hypoxic and nutrient gradients, self-organize, and have spatially varying phenotypes along the gradients, leading to new insights into tumorigenesis.

The influence of tumour fluorodeoxyglucose avidity and cachexia development on patient survival in oesophageal or gastroesophageal junction cancer.

Background and Aims: Cancer cachexia is manifested by loss in muscle, adipose, weight, and appetite. PET 18F-FDG uptake identifies tumor metabolic and inflammatory changes, potentially associated with cachexia development. We examined if primary gastroesophageal tumor 18F-FDG uptake correlates with cachexia development and survival in cancer patients. Methods: One hundred twenty-six esophageal (n=87) and gastroesophageal junction (n=39) cancer patients, with a median age at diagnosis of 63 years (IQR 54-71), evaluated between 2006-2014 with pre-treatment PET imaging and cachexia determination at diagnosis were included in the study cohort (22.1% female; 6.7%, 24.4%, 50.4%, and 18.5% with tumor stage I, II, III, and IV respectively). Maximum primary tumor standardized uptake values (SUVMax) were obtained and dichotomized based off the calculated cut-point SUVMax of 8.5 (P=.0018). Associations between survival, cachexia development and primary tumor 18F-FDG uptake were evaluated using univariate and multivariate analyses. Results: Cancer-associated weight loss (cachexia) and primary tumor SUVMax at or above the statistically determined cut-point of 8.5 were present in 54% and 57% of patients, respectively. Primary tumor SUVMax above the cut-point was significantly associated with pre-treatment cancer-associated weight loss (P=.0033) and, in multivariate analysis, correlated with a 2.3-fold increased risk of death (95% CI 1.4, 3.7; P=.0010). When divided into cohorts defined by their combined cachexia and high versus low SUVMax tumor status, positive cachexia status or/and high SUVMax tumors were associated with similar significant decrements in survival. Conclusion: A positive association was present between cancer-associated weight loss and SUVMax of the primary tumor, suggesting greater glycolytic metabolism in gastroesophageal tumors that induce cachexia. This interpretation of routinely administered PET scans could lead to earlier categorization of patients with cachexia-inducing tumors. Both cachexia and high SUVMax status were independently associated with worsened survival outcomes, further supporting their prognostic relevance in patients with gastroesophageal cancer.

Inducible nitric oxide synthase-derived extracellular nitric oxide flux regulates proinflammatory responses at the single cell level.

The role of nitric oxide (NO) in cancer progression has largely been studied in the context of tumor NOS2 expression. However, pro- versus anti-tumor signaling is also affected by tumor cell-macrophage interactions. While these cell-cell interactions are partly regulated by NO, the functional effects of NO flux on proinflammatory (M1) macrophages are unknown. Using a triple negative murine breast cancer model, we explored the potential role of macrophage Nos2 on 4T1 tumor progression. The effects of NO on macrophage phenotype were examined in bone marrow derived macrophages from wild type and Nos2-/- mice following in vitro stimulation with cytokine/LPS combinations to produce low, medium, and high NO flux. Remarkably, Nos2 induction was spatially distinct, where Nos2high cells expressed low cyclooxygenase-2 (Cox2) and vice versa. Importantly, in vitro M1 polarization with IFNγ+LPS induced high NO flux that was restricted to cells harboring depolarized mitochondria. This flux altered the magnitude and spatial extent of hypoxic gradients. Metabolic and single cell analyses demonstrated that single cell Nos2 induction limited the generation of hypoxic gradients in vitro, and Nos2-dependent and independent features may collaborate to regulate M1 functionality. It was found that Cox2 expression was important for Nos2high cells to maintain NO tolerance. Furthermore, Nos2 and Cox2 expression in 4T1 mouse tumors was spatially orthogonal forming distinct cellular neighborhoods. In summary, the location and type of Nos2high cells, NO flux, and the inflammatory status of other cells, such as Cox2high cells in the tumor niche contribute to Nos2 inflammatory mechanisms that promote disease progression of 4T1 tumors.

Calorie restriction for human aging: is there a potential benefit for cancer?

Caloric restriction in non-obese humans improves metabolic efficiency and reduces oxidative damage markers which may decrease cancer incidence and progression.

Exposure of fibrinogen and thrombin to nitric oxide donor ProliNONOate affects fibrin clot properties.

: Fibrin fibers form the structural backbone of blood clots. The structural properties of fibrin clots are highly dependent on formation kinetics. Environmental factors such as protein concentration, pH, salt, and protein modification, to name a few, can affect fiber kinetics through altered fibrinopeptide release, monomer association, and/or lateral aggregation. The objective of our study was to determine the effect of thrombin and fibrinogen exposed to nitric oxide on fibrin clot properties. ProliNONOate (5 µmol/l) was added to fibrinogen and thrombin before clot initiation and immediately following the addition of thrombin to the fibrinogen solution. Resulting fibrin fibers were probed with an atomic force microscope to determine their diameter and extensibility and fibrin clots were analyzed for clot density using confocal microscopy. Fiber diameters were also determined by confocal microscopy and the rate of clot formation was recorded using UV-vis spectrophotometry. Protein oxidation and S-nitrosation was determined by UV-vis, ELISA, and chemiluminescence. The addition of ProliNONOate to fibrinogen or thrombin resulted in a change in clot structure. ProliNONOate exposure produced clots with lower fiber density, thicker fibers, and increased time to maximum turbidity. The effect of the exposure of nitric oxide to thrombin and fibrinogen were measured independently and indicated that each plays a role in altering clot properties. We detected thrombin S-nitrosation and protein carbonyl formation after nitric oxide exposure. Our study reveals a regulation of fibrin clot properties by nitric oxide exposure and suggests a role of peroxynitrite in oxidative modifications of the proteins. These results relate nitric oxide bioavailability and oxidative stress to altered clot properties.