NGMA-6. Quantitative MGMT Promoter Methylation Index Indicates Non-Linear, Prognostic Effect in Glioblastoma

Background Epigenetic inhibition of the O6-methylguanine-DNA-methyltransferase (MGMT) gene has emerged as a clinically relevant prognostic marker in glioblastoma (GBM). Methylation of the MGMT promoter has been shown to increase chemotherapy efficacy. While traditionally reported as a binary marker, recent methodological advancements have led to quantitative methods of measuring methylation, allowing for clearer insights into methylation’s functional relationship with survival. Methods A CLIA assay and bisulfite sequencing was utilized to develop a quantitative, 17-point MGMT promoter methylation index derived from the number of methylated CpG sites. Retrospective review of 242 newly diagnosed GBM patients was performed in order to discern how risk for mortality transforms as promoter methylation increases. Non-linearities were captured by fitting splines to Cox proportional hazard models, plotting smoothed residuals, and creating survival plots. Covariates included age, KPS, IDH1 mutation, and extent of resection. Results Median follow-up time and progression free survival were 15.9 and 9 months, respectively. 176 subjects experienced death. A one-unit increase in CpG methylation resulted in a 4% reduction in hazard (95% CI 0.93–0.99, P<0.005). Moreover, GBM patients with low levels of methylation (1–6 CpG islands) fared markedly worse (HR=1.62, 95% CI 1.03–2.54, P<0.036) than individuals who were unmethylated (reference group). Subjects with medium levels of methylation (7–12 sites) had the greatest reduction in hazard (HR=0.48, 95% CI 0.29–0.80, P<0.004), followed by individuals in the highest methylation tertile (HR=0.62, 95% CI 0.40–0.97, P<0.035). Conclusion The extent of MGMT methylation shares a non-linear relationship with survival, suggesting conformation of the marker’s protective effect. This finding challenges the current understanding of MGMT and underlines the clinical importance of determining its prognostic utility. Potential limitations include censoring, sample size, and extraneous mutations. Future research is warranted to examine whether the location of CpG site methylation contributes to a reduction in mortality hazard.

Visual-Based Localization Using Pictorial Planar Objects in Indoor Environment

Localization is an important technology for smart services like autonomous surveillance, disinfection or delivery robots in future distributed indoor IoT applications. Visual-based localization (VBL) is a promising self-localization approach that identifies a robot’s location in an indoor or underground 3D space by using its camera to scan and match the robot’s surrounding objects and scenes. In this study, we present a pictorial planar surface based 3D object localization framework. We have designed two object detection methods for localization, ArPico and PicPose. ArPico detects and recognizes framed pictures by converting them into binary marker codes for matching with known codes in the library. It then uses the corner points on a picture’s border to identify the camera’s pose in the 3D space. PicPose detects the pictorial planar surface of an object in a camera view and produces the pose output by matching the feature points in the view with that in the original picture and producing the homography to map the object’s actual location in the 3D real world map. We have built an autonomous moving robot that can self-localize itself using its on-board camera and the PicPose technology. The experiment study shows that our localization methods are practical, have very good accuracy, and can be used for real time robot navigation.

Segregation of Familial Risk of Obesity in NHANES Cohort Supports a Major Role for Large Genetic Effects in the Current Obesity Epidemic

The continuing increase in many countries in adult body mass index (BMI kg/m2) and its dispersion is contributed to by interaction between genetic susceptibilities and an increasingly obesogenic environment (OE). The determinants of OE-susceptibility are unresolved, due to uncertainty around relevant genetic and environmental architecture. We aimed to test the multi-modal distributional predictions of a Mendelian genetic architecture based on collectively common, but individually rare, large-effect variants and their ability to account for current trends in a large population-based sample. We studied publicly available adult BMI data (n = 9102) from 3 cycles of NHANES (1999, 2005, 2013). A first degree family history of diabetes served as a binary marker (FH0/FH1) of genetic obesity susceptibility. We tested for multi-modal BMI distributions non-parametrically using kernel-smoothing and conditional quantile regression (CQR), obtained parametric fits to a Mendelian model in FH1, and estimated FH x OE interactions in CQR models and ANCOVA models incorporating secular time. Non-parametric distributional analyses were consistent with multi-modality and fits to a Mendelian model in FH1 reliably identified 3 modes. Mode separation accounted for ~40% of BMI variance in FH1 providing a lower bound for the contribution of large effects. CQR identified strong FH x OE interactions and FH1 accounted for ~60% of the secular trends in BMI and its SD in ANCOVA models. Multimodality in the FH effect is inconsistent with a predominantly polygenic, small effect architecture and we conclude that large genetic effects interacting with OE provide a better quantitative explanation for current trends in BMI.

Pre-Treatment p27 and Bcl-6 Staining Levels Correlate with Response to Bortezomib in Non-Hodgkin Lymphoma: Results from a Tissue Microarray Analysis

Background: Proteasome inhibitors (PI) affect a variety of intracellular processes, including the cell cycle, NF-kB and other signal transduction pathways, and the balance of bcl-2-related proteins, yet it remains unknown which of these targets are most crucial in determining response to PI treatment in non-Hodgkin Lymphoma (NHL). Responses to bortezomib (btz) have been seen in different NHL subtypes in several phase 2 studies. The consistency of response suggests that there may be biological characteristics that determine individual tumor responses to PIs. We used tissue microarray (TMA) technology to determine if pre-treatment tumor characteristics can predict outcome of btz treatment in NHL. Methods: TMAs were constructed using paraffin-embedded blocks of pre-treatment tissue from patients enrolled in a phase 2, CTEP-NCI sponsored trial of btz in NHL. Microsections were stained for 18 proteins with reported relevance to proteasome function and/or lymphoma prognosis. All stains were evaluated and scored by a central pathologist. Staining was correlated with quality and duration of response (DOR) or time to treatment failure (TTF). The best response was treated as a binary outcome (PR/CR vs SD/POD). Correlation between each marker and response was assessed by univariate analysis. The exact Wilcoxon rank-sum test was used to compare DOR and TTF with respect to the binary marker scores. Results: This analysis includes 35 of 75 patients treated with btz between 11/6/01 and 2/23/07 for whom pre-treatment tissue blocks could be obtained. Response data were available for 32 of these patients. Diagnoses include: FL (N=10), SLL (N=4), MCL (N=14) and MZL (N=4). Expression of the cell-cycle inhibitor p27 was more common in responding vs non-responding pts (p=0.024), and was also significantly associated with longer DOR (p=0.020) and longer TTF (p=0.021; figure). Presence of Bcl-6 was significantly associated with shorter DOR (p=0.049) and shorter TTF (p=0.048; figure), but not response. Conclusions: Using TMA analysis, we have shown that NHL patients with pre-treatment p27 staining were more likely to respond to btz, and had a longer DOR and TTF than those without baseline staining. Conversely, patients with baseline Bcl-6 expression had a shorter DOR and TTF than those without. Although the number of patients in this analysis is small, the data will help us generate hypotheses about disease and treatment biology that can be tested in larger studies. We are currently collecting samples from a broader pool of patients treated with btz at MSKCC to verify these results. TTF with bortezomib by (A) p27 and (B) Bcl-6 status. Figure. Figure.