Johnson, Geoffrey B.

AbstractBackground and AimsPositron emission tomography with computed tomography (PET/CT) has been used to detect metastasis in the diagnosis of esophageal adenocarcinoma (EAC). However, the utility of PET/CT to assess primary tumor for endoscopic resectability and prognosis in early EAC remains unclear. We conducted a retrospective study to determine the association of PET/CT findings with histopathological tumor invasion depth and survival outcomes.MethodsEAC patients who underwent PET/CT followed by endoscopic mucosal resection (EMR) were included. Pathology on EMR and survival outcomes from a prospectively maintained database was retrieved. Two radiologists independently reviewed the PET/CT using the following parameters: detection of malignancy, fluorodeoxyglucose (FDG) uptake intensity, FDG focality, FDG eccentricity, esophageal thickness, maximal standard uptake value (SUVmax), and SUVmax ratio (lesion/liver).ResultsThere were 72 eligible patients: 42 (58.3%) had T1a lesions, and 30 (41.7%) had ≥ T1b. Only SUVmax ratio was associated with tumor invasion depth (odds ratio = 2.77, 95% confidence interval 1.26–7.73, P = 0.0075). Using a cut‐off of 1.48, the sensitivity and specificity of SUVmax ratio for identification of T1a lesions were 43.3% and 80.9%, respectively. Adjusting the SUVmax ratio to 2.14, 16.7% (5/30) of ≥ T1b patients were identified without any false‐positive cases. Multivariate analysis showed SUVmax ratio, Charlson comorbidity index, and esophagectomy were independent predictors for survival.ConclusionsSUVmax ratio (lesion/liver) is more accurate in predicting endoscopic resectability and mortality for EAC than other PET/CT parameters and appears promising as a useful adjunct to the current diagnostic work‐up.

ABSTRACT Signaling through Toll‐like receptor 4 (TLR4) is thought to initiate innate and adaptive immune responses. Signaling of TLR4 is usually studied using isolated cells, which are activated by subnanomolar concentrations of lipopolysaccharide (LPS). However, in normal tissues, cells bearing TLR4 reside in microenvironments containing large amounts of endogenous substances that can stimulate the receptor. We developed an in vitro model system using the human cell line HEK 293 and an in vivo model using mice that have normal or that lack TLR4 receptors to study how TLR4 functions in such microenvironments. Here we report that signaling through TLR4 is strongly inhibited by intact extracellular matrix and that inhibition is abrogated and endogenous agonist(s) are liberated when the matrix is degraded. Thus, release from inhibition rather than direct stimulation by agonists such as LPS is the critical first event by which TLR4 initiates immune responses.

ABSTRACT Toll receptors in Drosophila contribute to host defense and establish the body plan. Mammalian homologues of Toll, the Toll‐like receptors (TLRs), are thought to function only in host defense. Here, we report that mice harboring mutations in TLR4 or in CD14, a co‐receptor for TLR4, have an “ideal” body plan consisting of increased bone mineral content, density, and size as well as decreased body fat. These mutant mice live long lives, have normal activity and fertility, and show no evidence of infection. Unlike many strains of caged wild‐type mice, they do not become obese. Although all mice continue to gain body fat, bone content, and overall weight, the difference in bone content and body fat between mutant and wild‐type mice increases with age. Thus, defects in TLR4/CD14 complex generate an “Adonis” phenotype, characterized by this ideal body type, and this function could potentially be exploited for the treatment of osteoporosis and obesity.