MLH1-rheMac hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques.

Over the past two decades, 33 cases of colonic adenocarcinomas have been diagnosed in rhesus macaques (Macaca mulatta) at the nonhuman primate colony of the Keeling Center for Comparative Medicine and Research at The University of Texas MD Anderson Cancer Center. The distinctive feature in these cases, based on PET/computed tomography (CT) imaging, was the presence of two or three tumor lesions in different locations, including proximal to the ileocecal juncture, proximal to the hepatic flexure, and/or in the sigmoid colon. These colon carcinoma lesions selectively accumulated [18F]fluorodeoxyglucose ([18F]FDG) and [18F]fluoroacetate ([18F]FACE) at high levels, reflecting elevated carbohydrate and fatty acid metabolism in these tumors. In contrast, the accumulation of [18F]fluorothymidine ([18F]FLT) was less significant, reflecting slow proliferative activity in these tumors. The diagnoses of colon carcinomas were confirmed by endoscopy. The expression of MLH1, MSH2, and MSH6 proteins and the degree of microsatellite instability (MSI) was assessed in colon carcinomas. The loss of MLH1 protein expression was observed in all tumors and was associated with a deletion mutation in the MLH1 promoter region and/or multiple single-nucleotide polymorphism (SNP) mutations in the MLH1 gene. All tumors exhibited various degrees of MSI. The pedigree analysis of this rhesus macaque population revealed several clusters of affected animals related to each other over several generations, suggesting an autosomal dominant transmission of susceptibility for colon cancer. The newly discovered hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques, termed MLH1-rheMac, may serve as a model for development of novel approaches to diagnosis and therapy of Lynch syndrome in humans.

Dependence of DCE-MRI biomarker values on analysis algorithm.

BACKGROUND: Dynamic contrast-enhanced MRI (DCE-MRI) biomarkers have proven utility in tumors in evaluating microvascular perfusion and permeability, but it is unclear whether measurements made in different centers are comparable due to methodological differences. PURPOSE: To evaluate how commonly utilized analytical methods for DCE-MRI biomarkers affect both the absolute parameter values and repeatability. MATERIALS AND METHODS: DCE-MRI was performed on three consecutive days in twelve rats bearing C6 xenografts. Endothelial transfer constant (Ktrans), extracellular extravascular space volume fraction (ve), and contrast agent reflux rate constant (kep) measures were computed using: 2-parameter ("Tofts" or "standard Kety") vs. 3-parameter ("General Kinetic" or "extended Kety") compartmental models (including blood plasma volume fraction (vp) with 3-parameter models); individual- vs. population-based vascular input functions (VIFs); and pixel-by-pixel vs. whole tumor-ROI. Variability was evaluated by within-subject coefficient of variation (wCV) and variance components analyses. RESULTS: DCE-MRI absolute parameter values and wCVs varied widely by analytical method. Absolute parameter values ranged, as follows, median Ktrans, 0.09-0.18 min-1; kep, 0.51-0.92 min-1; ve, 0.17-0.23; and vp, 0.02-0.04. wCVs also varied widely by analytical method, as follows: mean Ktrans, 32.9-61.9%; kep, 11.6-41.9%; ve, 16.1-54.9%; and vp, 53.9-77.2%. Ktrans and kep values were lower with 3- than 2-parameter modeling (p<0.0001); kep and vp were lower with pixel- than whole-ROI analyses (p<0.0006). wCVs were significantly smaller for ve, and larger for kep, with individual- than population-based VIFs. CONCLUSIONS: DCE-MRI parameter values and repeatability can vary widely by analytical methodology. Absolute values of DCE-MRI biomarkers are unlikely to be comparable between different studies unless analyses are carefully standardized.

Harderian gland adenectomy: a method to eliminate confounding radio-opacity in the assessment of rat brain metabolism by 18F-fluoro-2-deoxy-D-glucose positron emission tomography.

The 18F isotope of fluoro-2-deoxy-D-glucose (FDG) is a radiotracer commonly used in positron emission tomography (PET) for determining regional metabolic activity in the brain. However, in rats and many other species with nictitating membranes, harderian glands located just behind the eyes aggressively incorporate 18F-FDG to the extent that PET images of the brain become obscured. This radioactive spillover, or 'partial volume error,' combined with the limited spatial resolution of microPET scanners (1.5 to 2 mm) may markedly reduce the ability to quantify neuronal activity in frontal brain structures. Theoretically, surgical removal of the harderian glands before 18F-FDG injection would eliminate the confounding uptake of the radioactive tracer and thereby permit visualization of glucose metabolism in the frontal brain. We conducted a pilot study of unilateral harderian gland adenectomy, leaving the contralateral gland intact for comparison. At 1 wk after surgery, each rat was injected intravenously with 18F-FDG, and 40 min later underwent brain microPET for 20 min. Review of the resulting images showed that the frontal cortex on the surgical side was defined more clearly, with only background 18F-FDG accumulation in the surgical bed. Activity in the frontal cortex on the intact side was obscured by intense accumulation of 18F-FDG in the harderian gland. By reducing partial volume error, this simple surgical procedure may become a valuable tool for visualization of the frontal cortex of rat brain by 18F-FDG microPET imaging.