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RATIONALE AND OBJECTIVES: Glioblastoma image evaluation utilizes MRI contrast-enhanced, T1-weighted and non-contrast T2-weighted FLAIR acquisitions. Disease progression assessment relies on changes in tumor diameter, which correlate poorly with survival. To improve treatment monitoring in glioblastoma, we investigated serial voxel-wise comparison of anatomically-aligned FLAIR signal as an early predictor of GBM progression. MATERIALS AND METHODS: We analyzed longitudinal normalized FLAIR images (rFLAIR) from 52 subjects using voxel-wise Parametric Response Mapping (PRM) to monitor volume fractions of increased (PRM(rFLAIR+)), decreased (PRM(rFLAIR−)), or unchanged (PRM(rFLAIR0)) rFLAIR intensity. We determined response by rFLAIR between pre-treatment and 10 weeks post-treatment. Risk of disease progression in a subset of subjects (N=26) with stable disease or partial response as defined by Response Assessment in Neuro-Oncology (RANO) criteria was assessed by PRM(rFLAIR) between weeks 10 and 20 and continuously until the PRM(rFLAIR+) exceeded a defined threshold. RANO defined criteria were compared with PRM-derived outcomes for tumor progression detection. RESULTS: Patient stratification for progression-free survival (PFS) and overall survival (OS) was achieved at week 10 using RANO criteria (PFS: p

Parametric response mapping (PRM) is a novel computed tomography (CT) technology that has shown potential for assessment of bronchiolitis obliterans syndrome (BOS) after hematopoietic stem cell transplantation (HCT). The primary aim of this study was to evaluate whether variations in image acquisition under real-world conditions affect the PRM measurements of clinically diagnosed BOS. CT scans were obtained retrospectively from 72 HCT recipients with BOS and graft-versus-host disease from Fred Hutchinson Cancer Research Center, Karolinska Institute, and the University of Michigan. Whole lung volumetric scans were performed at inspiration and expiration using site-specific acquisition and reconstruction protocols. PRM and pulmonary function measurements were assessed. Patients with moderately severe BOS at diagnosis (median forced expiratory volume at 1 second [FEV1] 53.5% predicted) had similar characteristics between sites. Variations in site-specific CT acquisition protocols had a negligible effect on the PRM-derived small airways disease (SAD), that is, BOS measurements. PRM-derived SAD was found to correlate with FEV1% predicted and FEV1/ forced vital capacity (R = -0.236, P = .046; and R = -0.689, P < .0001, respectively), which suggests that elevated levels in the PRM measurements are primarily affected by BOS airflow obstruction and not CT scan acquisition parameters. Based on these results, PRM may be applied broadly for post-HCT diagnosis and monitoring of BOS.

Bipolar disorder (BD) is associated with a range of social cognitive deficits. This study investigated the functioning of the mentalizing brain system in BD probed by an eye gaze perception task during fMRI. Compared with healthy controls (n = 21), BD participants (n = 14) showed reduced preferential activation for self-directed gaze discrimination in the medial prefrontal cortex (mPFC) and temporo-parietal junction (TPJ), which was associated with poorer cognitive and social functioning. Aberrant functions of the mentalizing system should be further investigated as marker of social dysfunction and treatment targets.HighlightsSocial dysfunction in bipolar disorder (BD) may be due to altered mentalizing.Individuals with BD showed reduced activation in the mentalizing brain system.Aberrant activity of the mentalizing system was associated with poorer functioning.

Background Standardized definitions and methods of surveillance for local recurrence of nonmelanoma skin cancer are critical in determining cure rates attributed to treatment modalities. Objective We sought to offer a standard definition of local recurrence after surgical treatment of nonmelanoma skin cancer and to propose an acceptable surveillance period and tracking methods. Methods A literature search was performed for background definitions of local recurrence and tracking methods. The American College of Mohs Surgery (ACMS) Registry and Outcomes Committee then conducted a modified Delphi process to arrive at consensus definitions. Results We define local recurrence as a tumor with comparable histology, with contiguity to the surgical scar after treatment, and that arises within the area of the previously treated tumor. Limitations This project reports the results of a modified Delphi method process involving members of the ACMS. The model described may not be useful for nonexcision type treatments such as topical chemotherapy, electrodessication and curettage, or radiation treatment. Conclusions Previous definitions of recurrence and surveillance methods after surgical treatment of nonmelanoma skin cancer are variable and nonstandard. We describe consensus standards for defining and tracking recurrence that should allow for consistent scientific evaluation and development of performance data in skin cancer outcomes registries.

We consider modeling case-patterns under a complex spatial and longitudinal sampling design as conducted via a serial case–control study of diarrheal disease in northwestern Ecuador. We build a two-stage space-time model to understand the role of spatially and temporally referenced covariates that reflect social and natural environments in the sampled region, after accounting for unmeasured residual heterogeneities. All diarrheal case events are collected from 21 sampled communities in Esmeraldes province in Ecuador, during seven sampling cycles from 2003 to 2008. The region of interest comprises 158 communities along a river basin. Prediction of case counts at unsampled communities at a future time is of interest along with estimation of risk-related parameters. We propose a computationally feasible two-stage Bayesian approach to estimate the risk-related parameters and conduct predictive inference. We first apply the log Gaussian Cox process (LGCP), commonly used to model spatial clustering of point patterns, to accommodate temporal variation within the sampled communities. Prediction of the number of cases at unsampled communities at a future time is obtained by a disease mapping model conditional on the expected case counts from Stage I.

RATIONALE: Treatment of glioblastoma (GBM) remains challenging due in part to its histologic intratumoral heterogeneity that contributes to its overall poor treatment response. Our goal was to evaluate a voxel-based biomarker, the functional diffusion map (fDM), as an imaging biomarker to detect heterogeneity of tumor response in a radiation dose escalation protocol using a genetically engineered murine GBM model. EXPERIMENTAL DESIGN: Twenty-four genetically engineered murine GBM models [Ink4a-Arf-/-/Ptenloxp/loxp/Ntv-a RCAS/PDGF(+)/Cre(+)] were randomized in four treatment groups (n = 6 per group) consisting of daily doses of 0, 1, 2, and 4 Gy delivered for 5 days. Contrast-enhanced T1-weighted and diffusion-weighted magnetic resonance imaging (MRI) scans were acquired for tumor delineation and quantification of apparent diffusion coefficient (ADC) maps, respectively. MRI experiments were performed daily for a week and every 2 days thereafter. For each animal, the area under the curve (AUC) of the percentage change of the ADC (AUCADC) and that of the increase in fDM values (AUCfDM+) were determined within the first 5 days following therapy initiation. RESULTS: Animal survival increased with increasing radiation dose. Treatment induced a dose-dependent increase in tumor ADC values. The strongest correlation between survival and ADC measurements was observed using the AUCfDM+ metric (R2 = 0.88). CONCLUSION: This study showed that the efficacy of a voxel-based imaging biomarker (fDM) was able to detect spatially varying changes in tumors, which were determined to be a more sensitive predictor of overall response versus whole-volume tumor measurements (AUCADC). Finally, fDM provided for visualization of treatment-associated spatial heterogeneity within the tumor.

E26 transformation-specific (ETS) transcription factors are known to be involved in gene aberrations in various malignancies including prostate cancer; however, their role in melanoma oncogenesis has yet to be fully explored. We have completed a comprehensive fluorescence in situ hybridization (FISH)-based screen for all 27 members of the ETS transcription factor family on two melanoma tissue microarrays, representing 223 melanomas, 10 nevi, and 5 normal skin tissues. None of the melanoma cases demonstrated ETS fusions; however, 6 of 114 (5.3%) melanomas were amplified for ETV1 using a break-apart FISH probe. For the six positive cases, locus-controlled FISH probes revealed that two of six cases were amplified for the ETV1 region, whereas four cases showed copy gains of the entire chromosome 7. The remaining 26 ETS family members showed no chromosomal aberrations by FISH. Quantitative polymerase chain reaction showed an average 3.4-fold (P value = .00218) increased expression of ETV1 in melanomas, including the FISH ETV1-amplified cases, when compared to other malignancies (prostate, breast, and bladder carcinomas). These data suggest that a subset of melanomas overexpresses ETV1 and amplification of ETV1 may be one mechanism for achieving high gene expression.

To evaluate whether liver function can be assessed globally and spatially by using volumetric dynamic contrast-enhanced magnetic resonance imaging MRI (DCE-MRI) to potentially aid in adaptive treatment planning.Seventeen patients with intrahepatic cancer undergoing focal radiation therapy (RT) were enrolled in institution review board-approved prospective studies to obtain DCE-MRI (to measure regional perfusion) and indocyanine green (ICG) clearance rates (to measure overall liver function) prior to, during, and at 1 and 2 months after treatment. The volumetric distribution of portal venous perfusion in the whole liver was estimated for each scan. We assessed the correlation between mean portal venous perfusion in the nontumor volume of the liver and overall liver function measured by ICG before, during, and after RT. The dose response for regional portal venous perfusion to RT was determined using a linear mixed effects model.There was a significant correlation between the ICG clearance rate and mean portal venous perfusion in the functioning liver parenchyma, suggesting that portal venous perfusion could be used as a surrogate for function. Reduction in regional venous perfusion 1 month after RT was predicted by the locally accumulated biologically corrected dose at the end of RT (P.0007). Regional portal venous perfusion measured during RT was a significant predictor for regional venous perfusion assessed 1 month after RT (P.00001). Global hypovenous perfusion pre-RT was observed in 4 patients (3 patients with hepatocellular carcinoma and cirrhosis), 3 of whom had recovered from hypoperfusion, except in the highest dose regions, post-RT. In addition, 3 patients who had normal perfusion pre-RT had marked hypervenous perfusion or reperfusion in low-dose regions post-RT.This study suggests that MR-based volumetric hepatic perfusion imaging may be a biomarker for spatial distribution of liver function, which could aid in individualizing therapy, particularly for patients at risk for liver injury after RT.

Background Neuroimaging studies of emotion in schizophrenia have reported abnormalities in amygdala and other regions, although divergent results and heterogeneous paradigms complicate conclusions from single experiments. To identify more consistent patterns of dysfunction, a meta-analysis of functional imaging studies of emotion was undertaken. Methods Searching Medline and PsycINFO databases through January 2011, 88 potential articles were identified, of which 26 met inclusion criteria, comprising 450 patients with schizophrenia and 422 healthy comparison subjects. Contrasts were selected to include emotion perception and emotion experience. Foci from individual studies were subjected to a voxelwise meta-analysis using multilevel kernel density analysis. Results For emotional experience, comparison subjects showed greater activation in the left occipital pole. For emotional perception, schizophrenia subjects showed reduced activation in bilateral amygdala, visual processing areas, anterior cingulate cortex, dorsolateral frontal cortex, medial frontal cortex, and subcortical structures. Schizophrenia subjects showed greater activation in the cuneus, parietal lobule, precentral gyrus, and superior temporal gyrus. Combining across studies and eliminating studies that did not balance on effort and stimulus complexity eliminated most differences in visual processing regions as well as most areas where schizophrenia subjects showed a greater signal. Reduced reactivity of the amygdala appeared primarily in implicit studies of emotion, whereas deficits in anterior cingulate cortex activity appeared throughout all contrasts. Conclusions Processing emotional stimuli, schizophrenia patients show reduced activation in areas engaged by emotional stimuli, although in some conditions, schizophrenia patients exhibit increased activation in areas outside those traditionally associated with emotion, possibly representing compensatory processing.

Background & Aims Dysplasia is a premalignant condition in Barrett's esophagus that is difficult to detect on endoscopy because of its flat architecture and patchy distribution. Peptides are promising for use as novel molecular probes that identify cell surface targets unique to disease and can be fluorescence-labeled for detection. We aim to select and validate an affinity peptide that binds to esophageal dysplasia for future clinical studies. Methods Peptide selection was performed using phage display by removing nonspecific binders using Q-hTERT (intestinal metaplasia) cells and achieving specific binding against OE33 (esophageal adenocarcinoma) cells. Selective binding was confirmed on bound phage counts, enzyme-linked immunosorbent assay (ELISA), flow cytometry, competitive inhibition, and fluorescence microscopy. On stereomicroscopy, specific peptide binding to dysplasia on endoscopically resected specimens was assessed by rigorous registration of fluorescence intensity to histology in 1-mm intervals. Results The peptide sequence SNFYMPL was selected and showed preferential binding to target cells. Reduced binding was observed on competition with unlabeled peptide in a dose-dependent manner, an affinity of K d = 164 nmol/L was measured, and peptide binding to the surface of OE33 cells was validated on fluorescence microscopy. On esophageal specimens (n = 12), the fluorescence intensity (mean ± SEM) in 1-mm intervals classified histologically as squamous (n = 145), intestinal metaplasia (n = 83), dysplasia (n = 61), and gastric mucosa (n = 69) was 46.5±1.6, 62.3±5.8, 100.0±9.0, and 42.4 ± 3.0 arb units, respectively. Conclusions The peptide sequence SNFYMPL binds specifically to dysplasia in Barrett's esophagus and can be fluorescence labeled to target premalignant mucosa on imaging.

We present a Bayesian bivariate image model and apply it to a study that was designed to investigate the relationship between hypoxia and angiogenesis in an animal tumor model. Two radiolabeled tracers (one measuring angiogenesis, the other measuring hypoxia) were simultaneously injected into the animals, the tumors were removed and autoradiographic images of the tracer concentrations were obtained. We model correlation between tracers with a mixture of bivariate normal distributions and the spatial correlation inherent in the images by means of the Potts model. Although the Potts model is typically used for image segmentation, we use it solely as a device to account for spatial correlation. The number of classes in the model is assumed unknown and is estimated via reversible jump MCMC, marginalizing over the number of classes for posterior inference. We present the model and estimation method using set theory notation which will assist us in introducing a novel reallocation scheme used in the reversible jump proposals. We also estimate the spatial regularization parameter in the Potts model prior. Via simulation studies, we show that it is necessary to account for both the spatial correlation and the correlation between the two tracers.

Cluster extent and voxel intensity are two widely used statistics in neuroimaging inference. Cluster extent is sensitive to spatially extended signals while voxel intensity is better for intense but focal signals. In order to leverage strength from both statistics, several nonparametric permutation methods have been proposed to combine the two methods. Simulation studies have shown that of the different cluster permutation methods, the cluster mass statistic is generally the best. However, to date, there is no parametric cluster mass inference method available. In this paper, we propose a cluster mass inference method based on random field theory (RFT). We develop this method for Gaussian images, evaluate it on Gaussian and Gaussianized t-statistic images and investigate its statistical properties via simulation studies and real data. Simulation results show that the method is valid under the null hypothesis and demonstrate that it can be more powerful than the cluster extent inference method. Further, analyses with a single-subject and a group fMRI dataset demonstrate better power than traditional cluster extent inference, and good accuracy relative to a gold-standard permutation test.

RATIONALE AND OBJECTIVES: Integral to the mission of the National Institutes of Health-sponsored Lung Imaging Database Consortium is the accurate definition of the spatial location of pulmonary nodules. Because the majority of small lung nodules are not resected, a reference standard from histopathology is generally unavailable. Thus assessing the source of variability in defining the spatial location of lung nodules by expert radiologists using different software tools as an alternative form of truth is necessary.MATERIALS AND METHODS: The relative differences in performance of six radiologists each applying three annotation methods to the task of defining the spatial extent of 23 different lung nodules were evaluated. The variability of radiologists' spatial definitions for a nodule was measured using both volumes and probability maps (p-map). Results were analyzed using a linear mixed-effects model that included nested random effects.RESULTS: Across the combination of all nodules, volume and p-map model parameters were found to be significant at P CONCLUSION: Radiologists represent the major source of variance as compared with drawing tools independent of drawing metric used. Although the random noise component is larger for the p-map analysis than for volume estimation, the p-map analysis appears to have more power to detect differences in radiologist-method combinations. The standard deviation of the volume measurement task appears to be proportional to nodule volume.

Matrix metalloproteinases (MMPs) with collagenolytic and gelatinolytic activities are up-regulated in basal cell carcinoma. In the present study we demonstrate that the major collagenolytic enzyme detected is MMP-1 (interstitial collagenase) while gelatinolytic enzymes include both MMP-2 (72-kDa gelatinase A) and MMP-9 (92-kDa gelatinase B). Significant fractions of all three enzymes are present as active forms. In spite of the fact that high levels of gelatinolytic enzymes are present, the major fragmentation products resulting from digestion of intact type I collagen are the 1/4 and 3/4 fragments (products of MMP-1-mediated digestion). Thus, it appears that the gelatinolytic enzymes are not capable of degrading the collagen fragments as rapidly as they are produced. Since previous studies have demonstrated that interaction of interstitial fibroblasts with high molecular weight fragments of type I collagen leads to increased MMP production, the present results suggest a mechanism underlying altered function of stromal elements in the connective tissue adjacent to the growing neoplasm.

The field of exact analysis of independent discrete outcomes data with covariates has come of age in the recent years. Development of efficient numerical algorithms has been the prime factor fueling the growth. Exact inference on correlated or time-varying discrete data, on the other hand, has garnered little attention. In this paper, we lay the foundation for exact analysis for one class of longitudinal data problems – Markov chain models with covariates. In particular, we focus on a two-state first-order stationary Markov chain model with a multi-level stratification factor and a binary covariate of interest. We show that exact distributions for such models derive from conditional convolutions of elemental Bose–Einstein distributions. We develop a recursive polynomial multiplication algorithm with checks for infeasibility to compute such distributions, and empirically demonstrate its efficiency. We utilize the algorithm to compare exact inference on Markov chain data with the traditional large sample method. Given the transition counts, the latter method is insensitive as to whether the data are generated from a few long chains or many short chains. The exact method takes this feature into account. Our findings point towards a potential problem with large sample inference, namely the use of observed instead of expected information in finite samples. This issue needs further study. It is also seen that with Markov chain data, inferences drawn from the exact method may differ from that from the asymptotic method at transition count values that may not be deemed small.

Melanoma cells express ganglioside antigens GM3, GD3, GM2, and GD2 on their surface. This study examined whether immunization with a melanoma cell vaccine induced anti-ganglioside antibody responses in melanoma patients and whether these responses were correlated with survival. Sixty-six patients who had received melanoma cell vaccine immunotherapy after surgical removal of regional metastatic melanoma were identified. Cryopreserved serum samples from these patients were used in an enzyme-linked immunsorbent assay to determine the IgM antibody levels to GM2, GD2, GM3, and GD3 prior to melanoma cell vaccine treatment and 4 wk after the first melanoma cell vaccine immunization. All antibody levels significantly increased by week 4 (p < 0.001 for all four antibodies) and all increases were significantly associated with survival (anti-GD2, p < 0.001; anti-GM2, p = 0.001; anti-GD3, p < 0.001; anti-GM3, p < 0.001). Anti-tumor activity of these antibodies was proved using five representative antibody-positive sera in a complement-dependent cytotoxicity assay with cultured melanoma cell lines. These studies suggest that GM2, GD2, GM2, and GD3 expressed by melanoma cells can induce specific IgM antibodies and that high levels of these antibodies might have a beneficial impact on survival.

Background: Obesity is a chronic disease that has become one of the most serious health problems in Western society. Objective: We assessed the long-term effects of an energy-restricted diet combined with I or 2 daily meal replacements on body weight and biomarkers of disease risk in 100 obese patients. Design: Phase I consisted of a 3-mo, prospective, randomized, parallel intervention study of 2 dietary interventions to reduce weight. The energy-restricted diet (5.2-6.3 MJ/d) consisted of conventional foods (group A) or an isoenergetic diet with 2 meals and 2 snacks replaced daily by energy-controlled, vitamin-and-mineral-supplemented prepared foods (group B). Phase 2 consisted of a 24-mo. case-control. weight-maintenance study with an energy-restricted diet and I meal and I snack replaced daily for all patients. Results: Total weight loss (as a percentage of initial body weight) was 5.9 ± 5.0% in group A and 11.3 ± 6.8% in group B (P < 0.0001). During phase I. mean weight loss in group B (n = 50) was 7.1 ± 3.5 kg, with significant reductions in plasma triacylglycerol. glucose, and insulin concentrations (P < 0.0001). Group A patients (n = 50) lost an average of 1.3 ± 2.2 kg with no significant improvements in these biomarkers. During phase 2, both groups lost on average an additional 0.07% of their initial body weight every month (P < 0.01). During the 27-mo study, both groups experienced significant reductions in systolic blood pressure and plasma concentrations of triacylglycerol. glucose, and insulin (P < 0.01). Conclusion: These findings support the hypothesis that defined meal replacements can be used for successful, long-term weight control and improvements in certain biomarkers of disease risk.

Rationale and Objectives. We quantified differences in the detection of simulated lung nodules on computed radiographs on the basis of variations in nodule size, local contrast, body habitus (global contrast), and exposure. Methods. A step-wedge phantom was developed to simulate the attenuation ranges of the lung, retrocardiac, and subdiaphragmatic regions of the adult human chest. Additional Lucite wedges were used to simulate two different body thicknesses and to provide variable structural noise. Soft-tissue-equivalent nodules of 3-mm and 5-mm diameter that resulted in 10% differences in attenuation from lung equivalence were embedded in lung-equivalent material. By superimposing the sheets in various positions, 84 unique nodule configurations containing eight nodules per image were exposed on a computed radiography system. Computed radiographs were acquired at two different exposures approximating standard exposure and underexposure. For each resulting phantom image, seven observers scored the presence or absence of a nodule within individual cells of a 5 × 5 grid matrix. Results. True-positive fractions for 3-mm-diameter nodules were very low across all conditions. True-positive fractions for 5-mm-diameter nodules varied from 0.23 to 0.98. Significant differences in the conspicuity of 5-mm nodules depended on differences in phantom thickness and differences in the locations of nodules within lung-, retrocardiac-, or subdiaphragmatic-equivalent regions. Accuracy in detecting nodules was significantly lower at lower exposures when nodules were located in the subdiaphragmatic-equivalent region. Conclusion. On computed radiographs, small nodules (5-mm diameter) can be reliably detected when they are located in areas of high or moderate surrounding local contrast, such as the lung or mediastinal regions. Detection of nodules decreases in regions of lower optical density corresponding to the subdiaphragmatic regions of the chest. The decrease in nodule detectability is greatest under conditions that simulate large body thickness and underexposure.

We present a comparison of two efficient algorithms for exact analysis of an unordered 2 × K table. First, by considering conditional generating functions, we show that both the network algorithm of Mehta and Patel ( J. Amer. Statist. Assoc. 78 (1983)) and the fast Fourier transform (FFT) algorithm of Baglivo et al. ( J. Amer. Statist. Assoc. 82 (1992)) rest on the same foundation. This foundation is a recursive polynomial relation. We further show that the network algorithm is equivalent to a stage-wise implementation of this recursion while the FFT algorithm is based on performing the same recursion at complex roots of unity. Our empirical results for the Pearson X 2 , likelihood ratio, and Freeman-Halton statistics show that the network algorithm, or equivalently, the recursive polynomial multiplication algorithm is superior to the FFT algorithm with respect to computing speed and accuracy.