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Background Prognostic modeling in health care has been predominantly statistical, despite a rapid growth of literature on machine-learning approaches in biological data analysis. We aim to assess the relative importance of variables in predicting overall survival among patients with non-small cell lung cancer using a Variable Importance (VIMP) approach in a machine-learning Random Survival Forest (RSF) model for posttreatment planning and follow-up. Methods A total of 935 non-small cell lung cancer patients were randomly and equally divided into 2 training and testing cohorts in an RFS model. The prognostic variables included age, sex, race, the TNM Classification of Malignant Tumors (TNM) stage, smoking history, Eastern Cooperative Oncology Group performance status, histologic type, treatment category, maximum standard uptake value of whole-body tumor (SUVmaxWB), whole-body metabolic tumor volume (MTVwb), and Charlson Comorbidity Index. The VIMP was calculated using a permutation method in the RSF model. We further compared the VIMP of the RSF model to that of the standard Cox survival model. We examined the order of VIMP with the differential functional forms of the variables. Results In both the RSF and the standard Cox models, the most important variables are treatment category, TNM stage, and MTVwb. The order of VIMP is more robust in RSF model than in Cox model regarding the differential functional forms of the variables. Conclusions The RSF VIMP approach can be applied alongside with the Cox model to further advance the understanding of the roles of prognostic factors, and improve prognostic precision and care efficiency.

T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbored PD-L1/PD-L2 copy gain or amplification in 64% of cases, which was associated with increased PD-L1 expression (P = .0111). By directed and unsupervised spatial analyses of multiparametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune "neighborhoods" in which malignant B cells are surrounded by exceptionally high numbers of PD-L1-expressing TAMs and PD-1+ T cells. Furthermore, unbiased clustering of spatially resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in 3 of 5 patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies (NCT03316573; NCT01953692), including 2 complete responses and 1 partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL and also support the potential utility of spatially resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types.

PURPOSE: We hypothesized that whole-body metabolic tumor volume (MTVwb) could be used to supplement non-small cell lung cancer (NSCLC) staging due to its independent prognostic value. The goal of this study was to develop and validate a novel MTVwb risk stratification system to supplement NSCLC staging. METHODS: We performed an IRB-approved retrospective review of 935 patients with NSCLC and FDG avid tumor divided into modeling and validation cohorts based on the PET/CT scanner type used for imaging. In addition, sensitivity analysis was conducted by dividing the patient population into two randomized cohorts. Cox regression and Kaplan-Meier survival analyses were performed to determine the prognostic value of the MTVwb risk stratification system. RESULTS: The cutoff values (10.0, 53.4 and 155.0 mL) between the MTVwb quartiles of the modeling cohort were applied to both modeling and validation cohorts to determine each patient’s MTVwb risk stratum. The survival analyses showed that a lower MTVwb risk stratum was associated with better overall survival (all p

Currently, individual clinical prognostic variables are used sequentially with risk-stratification after TNM staging in clinical practice for the prognostic assessment of patients with NSCLC, which is not effective for estimating the collective impact of multiple individual variables on patient outcomes. Here, we developed a clinical and PET/CT volumetric prognostic (CPVP) index that integrates the prognostic power of multiple clinical variables and metabolic tumor volume from baseline FDG-PET, for use immediately after definitive therapy.This retrospective cohort study included 998 NSCLC patients diagnosed between 2004 and 2017, randomly assigned to two cohorts for modeling the CPVP index using Cox regression models examining overall survival (OS) and subsequent validation.The CPVP index generated from the model cohort included pretreatment variables (whole-body metabolic tumor volume [MTVwb], clinical TNM stage, tumor histology, performance status, age, race, gender, smoking history) and treatment type. A clinical variable (CV) index without MTVwb and PET/CT volumetric prognostic (PVP) index without clinical variables were also generated for comparison. In the validation cohort, univariate Cox modeling showed a significant association of the index with overall survival (OS; Hazard Ratio [HR] 3.14; 95% confidence interval [95% CI] = 2.71 to 3.65,The CPVP index for NSCLC patients has moderately strong prognostic power and is more prognostic than its individual prognostic variables and other indices. It provides a practical tool for quantitative prognostic assessment after initial treatment and therefore may be helpful for the development of individualized treatment and monitoring strategy for NSCLC patients.

Stage IIIA non-small cell lung cancer (NSCLC) is heterogeneous in tumor burden, and its treatment is variable. Whole-body metabolic tumor volume (MTVWB) has been shown to be an independent prognostic index for overall survival (OS). However, the potential of MTVWB to risk-stratify stage IIIA NSCLC has previously been unknown. If we can identify subgroups within the stage exhibiting significant OS differences using MTVWB, MTVWB may lead to adjustments in patients’ risk profile evaluations and may, therefore, influence clinical decision making regarding treatment. We estimated the risk-stratifying capacity of MTVWB in stage IIIA by comparing OS of stratified stage IIIA with stage IIB and IIIB NSCLC. We performed a retrospective review of 330 patients with clinical stage IIB, IIIA, and IIIB NSCLC diagnosed between 2004 and 2014. The patients’ clinical TNM stage, initial MTVWB, and long-term survival data were collected. Patients with TNM stage IIIA disease were stratified by MTVWB. The optimal MTVWB cutoff value for stage IIIA patients was calculated using sequential log-rank tests. Univariate and multivariate cox regression analyses and Kaplan-Meier OS analysis with log-rank tests were performed. The optimal MTVWB cut-point was 29.2 mL for the risk-stratification of stage IIIA. We identified statistically significant differences in OS between stage IIB and IIIA patients (p

The staging and management of patients with newly diagnosed nonsmall cell lung cancer (NSCLC) in the setting of recently diagnosed other (metachronous or synchronous) primary cancer are challenging. This retrospective cohort study was carried out to test our hypothesis that baseline 2-deoxy-2-[F]fluoro-D-glucose (F-FDG) PET/CT parameters, including whole-body metabolic tumor volume (MTVWB), total lesion glycolysis (TLGWB), and maximum standardized uptake value (SUVmaxWB), are associated with the overall survival (OS) of such patients.A total of 110 NSCLC patients (52 men and 58 women, aged 68.6±7.8 years) with other primary malignant cancers who had baseline F-FDG PET/CT scans were retrospectively reviewed. MTVWB, TLGWB, and SUVmaxWB were measured. Kaplan-Meier analysis with the log-rank test and Cox regression models were used to assess the association of OS with F-FDG PET/CT parameters and clinical risk factors.Kaplan-Meier analysis and univariate Cox regression models showed significant associations of OS with ln(MTVWB), ln(TLGWB), ln(SUVmaxWB), TNM stage, and treatment type (surgery vs. no treatment). Multivariable Cox regression models showed a significant relationship of OS with ln(MTVWB) [hazard ratio (HR)=1.368, P=0.001], ln(TLGWB) (HR=1.313, P0.001), and ln(SUVmaxWB) (HR=1.739, P=0.006), adjusted for age, treatment type, tumor histology, and TNM stage. The TNM stage was not associated significantly with OS when MTVWB, TLGWB, or SUVmaxWB were included in the multivariable models.MTVWB, TLGWB, and SUVmaxWB from baseline F-FDG PET/CT are associated individually with OS of patients with both NSCLC and other primary malignant tumors independent of age, treatment type, tumor histology, and TNM stage.

Objectives Whole-body metabolic tumor volume (MTVWB) and TNM staging are independent prognostic factors for overall survival (OS) in non-small cell lung cancer (NSCLC). We aimed to update and validate the PET/CT volumetric prognostic index (PVP index) using the new 8th edition TNM staging system to evaluate its prognostic power versus TNM staging and MTVWB alone. Materials and Methods This study was a retrospective analysis of 949 non-small cell lung cancer (NSCLC) patients diagnosed between 2004 and 2014. Clinical TNM stage, MTVWB, age and gender, tumor histology type at the initial staging PET/CT exam, as well as treatment history and long-term survival data were obtained. Patients were randomly assigned to modeling or validation group. Univariate and multivariate Cox regression analyses were performed to compare PVP index, TNM stage, and MTVWB in the validation group. Results The updated PVP index included the 3 variables TNM stage, and MTVWB and age. Univariate Cox models showed significant association of PVP index with overall survival (OS) in patients with NSCLC (with Hazard ratio HR = 2.88 in the validation group, p Conclusions The updated PVP index provides a quantitative risk assessment for NSCLC patients using 8th edition TNM staging, MTVWB, and age. The index provides a simple and practical way for the care team to incorporate the independent prognostic value of both the TNM stage and MTVWB. This approach can further improve the accuracy of overall survival prognosis.

To test the hypothesis that whole-body metabolic tumor burden (MTBWB) on postsurgical fluorodeoxyglucose (FDG) positron emission tomographic (PET)/computed tomographic (CT) images in patients with non-small cell lung cancer (NSCLC) is associated with their overall survival (OS).The institutional review board approved this study and waived the requirement for obtaining informed consent. One hundred forty-two patients with NSCLC (69 men, 73 women; median age, 67.7 years) who underwent postsurgical FDG PET/CT were retrospectively reviewed. The whole-body metabolic tumor volume (MTVWB), whole-body total lesion glycolysis (TLGWB), and whole-body maximum standardized uptake value (SUVWBmax) were measured. OS served as the primary end point of the study. Kaplan-Meier curves and Cox regression were used to assess the association between PET/CT markers and OS.The interobserver variability was low, as demonstrated with intraclass correlation coefficients higher than 0.94 for SUVWBmax, MTVWB, and TLGWB. When compared with those with negative postsurgical FDG PET/CT findings, a significant decrease of OS was found in patients with the presence of FDG-avid tumor on the basis of both a log-rank test (P = .001) and a univariate Cox model (hazard ratio = 2.805, P = .001). In patients with FDG-avid tumor, there was a significant association between OS and ln MTVWB (P.001), ln TLGWB (P.001), and ln SUVWBmax (P.010) in either univariate or multivariate analysis, after adjusting for patient age, sex, TNM restage, and therapy after postsurgical PET/CT studies. The OS differences between the groups dichotomized by the median value of MTVWB (11.54 mL, P = .004), TLGWB (32.38 mL, P.001), or SUVWBmax (4.93, P = .023) were significant.MTBWB and tumor maximum standardized uptake at postsurgical FDG PET/CT are related to the patient's OS in NSCLC, independent of age, sex, TNM restaging, and therapy after postsurgical PET/CT studies.

Background No study to test the feasibility and prognostic value of the number of primary tumors, the number of positive lymph nodes, and the total number of tumors in the whole body as tumor burden measurements on FDG PET/CT imaging has been reported. Purpose To determine whether the number of tumors seen in 18F-FDG PET scans can be a prognostic factor in non-surgical patients with non-small cell lung cancer (NSCLC). Material and Methods One hundred and forty patients with histologically proven NSCLC and baseline 18F-FDG PET scan before therapy were identified in this retrospective analysis. The total number of tumors (TTn) in the whole body, the number of primary tumors (Tn), positive lymph nodes (Nn), and distant metastases (Mn), along with the maximum standardized uptake values (SUVmax) of the tumors were measured. Inter-observer variability of the total number of tumors, counted by two radiologists, was assessed. Survival analyses were performed to determine the prognostic value of the number of tumors. Results Concordance correlation coefficients for the TTn, Tn, Nn, and Mn were all greater than 0.85. TTn and Nn were strong prognostic factors of NSCLC patients' overall survival (OS). In univariate Cox regression models, gender, stage, TTn, Nn, and Mn were statistically significant factors ( P = 0.016, 0.032, , respectively, after adjusting for clinical stage based 7th edition of TNM staging system, age, gender, and SUVmax. Patients with a TTn ≤4 (cutpoint based on median value) had a median OS of 15.2 months compared with 9.0 months for those with TTn >4. Conclusion Measuring the number of tumors on FDG PET imaging is easy to perform with minimal inter-observer variability. The total number of tumors and number of nodal metastases, as metabolic tumor burden measurements in 18F-FDG PET/CT, are prognostic markers independent of clinical stage, age, gender, and SUV measurement in non-surgical patients with NSCLC.

The objective of this study was to assess the prognostic value of metabolic tumor burden on 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) positron emission tomography (PET)/CT measured with metabolic tumor volume (MTV) and total lesion glycolysis (TLG), independent of Union Internationale Contra la Cancrum (UICC)/American Joint Committee on Cancer (AJCC) tumor, node, and metastasis (TNM) stage, in comparison with that of standardized uptake value (SUV) in nonsurgical patients with non-small cell lung cancer (NSCLC).This study retrospectively reviewed 169 consecutive nonsurgical patients (78 men, 91 women, median age of 68 years) with newly diagnosed NSCLC who had pretreatment (18)F-FDG PET/CT scans. The (18)F-FDG PET/CT scans were performed in accordance with National Cancer Institute guidelines. The MTV of whole-body tumor (MTV(WB)), of primary tumor (MTV(T)), of nodal metastases (MTV(N)), and of distant metastases (MTV(M)); the TLG of whole-body tumor (TLG(WB)), of primary tumor (TLG(T)), of nodal metastases (TLG(N)), and of distant metastases (TLG(M)); the SUV(max) of whole-body tumor (SUV(maxWB)), of primary tumor (SUV(maxT)), of nodal metastases (SUV(maxN)), and of distant metastases (SUV(maxM)) as well as the SUV(mean) of whole-body tumor (SUV(meanWB)), of primary tumor (SUV(meanT)), of nodal metastases (SUV(meanN)), and of distant metastases (SUV(meanM)) were measured with the PETedge tool on a MIMvista workstation with manual adjustment. The median follow-up among survivors was 35 months from the PET/CT (range 2-82 months). Statistical methods included Kaplan-Meier curves, Cox regression, and C-statistics.There were a total of 139 deaths during follow-up. Median overall survival (OS) was 10.9 months [95% confidence interval (CI) 9.0-13.2 months]. The MTV was statistically associated with OS. The hazard ratios (HR) for 1 unit increase of ln(MTV(WB)), √(MTV(T)), √(MTV(N)), and √(MTV(M)) before/after adjusting for stage were: 1.47/1.43 (p0.001/0.001), 1.06/1.05 (p0.001/0.001), 1.11/1.10 (p0.001/0.001), and 1.04/1.03 (p = 0.007/0.043), respectively. TLG had statistically significant associations with OS with the HRs for 1 unit increase in ln(TLG(WB)), √(TLG(T)), √(TLG(N)), and √(TLG(M)) before/after adjusting for stage being 1.36/1.33 (p0.001/0.001), 1.02/1.02 (p = 0.001/0.002), 1.05/1.04 (p0.001/0.001), and 1.02/1.02 (p = 0.003/0.024), respectively. The ln(SUV(maxWB)) and √(SUV(maxN)) were statistically associated with OS with the corresponding HRs for a 1 unit increase before/after adjusting for stage being 1.46/1.43 (p = 0.013/0.024) and 1.22/1.16 (p = 0.002/0.040). The √(SUV(meanN)) was statistically associated with OS before and after adjusting for stage with HRs for a 1 unit increase of 1.32 (p0.001) and 1.24 (p = 0.015), respectively. The √(SUV(meanM)) and √(SUV(maxM)) were statistically associated with OS before adjusting for stage with HRs for a 1 unit increase of 1.26 (p = 0.017) and 1.18 (p = 0.007), respectively, but not after adjusting for stage (p = 0.127 and 0.056). There was no statistically significant association between OS and √(SUV(maxT)), ln(SUV(meanWB)), or √(SUV(meanT)). There was low interobserver variability among three radiologists with intraclass correlation coefficients (ICC) greater than 0.94 for SUV(maxWB), ln(MTV(WB)), and ln(TLG(WB)). Interobserver variability was higher for SUV(meanWB) with an ICC of 0.806.Baseline metabolic tumor burdens at the level of whole-body tumor, primary tumor, nodal metastasis, and distant metastasis as measured with MTV and TLG on FDG PET are prognostic measures independent of clinical stage with low inter-observer variability and may be used to further stratify nonsurgical patients with NSCLC. This study also suggests MTV and TLG are better prognostic measures than SUV(max) and SUV(mean). These results will need to be validated in larger cohorts in a prospective study.

Objective To determine the accuracy of nonattenuation corrected (NAC) 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) images in the evaluation of solitary pulmonary lesion as compared with more established methods. Methods Fifty-six patients received 18F-FDG PET/CT for diagnosing solitary pulmonary nodules or mass lesions based on histopathology (n=39) and clinical follow-up (n=17). Visual pulmonary lesion FDG uptake was graded by consensus of two nuclear medicine physicians on both attenuation corrected (AC) [absent, less than mediastinal blood pool (MBP), equal to MBP, greater than MBP] and NAC (absent, less than skin, equal to skin, greater than skin) images. Standardized uptake values (SUV) were also measured from AC images. SUV, visual AC, and visual NAC methods' diagnostic performances were compared, distinguishing benign from malignant pulmonary nodules. Results There were 34 malignant and 22 benign lesions. Lesion diameter varied from 5 to 100 mm (mean±SD, 24.0±17.9 mm). The NAC, AC, and SUV method sensitivities and specificities were 100/64%, 91/59%, and 79/77%, respectively. For lesions less than 3 cm, NAC, AC, and SUV methods yielded accuracies of 85%, 78%, and 73%, respectively. The NAC method was the most sensitive and accurate especially for small nodules. Conclusion Visual assessment of NAC 18F-FDG PET images alone may provide a more accurate characterization of solitary pulmonary lesions.

In order to aid radiologists’ routine work for interpreting bone scan images, we developed a computerized method for temporal subtraction (TS) images which can highlight interval changes between successive whole-body bone scans, and we performed a prospective clinical study for evaluating the clinical utility of the TS images. We developed a TS image server which includes an automated image-retrieval system, an automated image-conversion system, an automated TS image-producing system, a computer interface for displaying and evaluating TS images with five subjective scales, and an automated data-archiving system. In this study, the radiologist could revise his/her report after reviewing the TS images if the findings on the TS image were confirmed retrospectively on our clinical picture archiving and communication system. We had 256 consenting patients of whom 143 had two or more whole-body bone scans available for TS images. In total, we obtained TS images successfully in 292 (96.1%) pairs and failed to produce TS images in 12 pairs. Among the 292 TS studies used for diagnosis, TS images were considered as “extremely beneficial” or “somewhat beneficial” in 247 (84.6%) pairs, as “no utility” in 44 pairs, and as “somewhat detrimental” in only one pair. There was no TS image for any pairs that was considered “extremely detrimental.” In addition, the radiologists changed their initial reported impression in 18 pairs (6.2%). The benefit to the radiologist of using TS images in the routine interpretation of successive whole-body bone scans was significant, with negligible detrimental effects.

OBJECTIVES The objective of this study was to test the hypothesis that the metabolic tumor volume (MTV) of primary non-small-cell lung cancer is not sensitive to differences in F-fluorodeoxyglucose (F-FDG) uptake time, and to compare this consistency of MTV measurements with that of standardized uptake value (SUV) and total lesion glycolysis (TLG). METHODS Under Institutional Review Board approval, 134 consecutive patients with histologically proven non-small-cell lung cancer underwent F-FDG PET/computed tomography scanning at about 1 h (early) and 2 h (delayed) after intravenous injection of F-FDG. MTV, SUV, and TLG of the primary tumor were all measured. Student's t-test and Wilcoxon's signed-rank test for paired data were used to compare MTV, SUV, and TLG between the two scans. The intraclass correlation coefficient (ICC) was used to assess agreement in PET parameters between the two scans and between the measurements made by two observers. RESULTS MTV was not significantly different (P=0.17) between the two scans. However, SUVmax, SUVmean, SUVpeak, and TLG increased significantly from the early to the delayed scans (P

Rationale and Objectives We evaluated the usefulness of temporal subtraction images obtained from two successive whole-body bone scans, in terms of improvement in radiologists’ diagnostic accuracy in detecting interval changes and of a reduction in reading time, by use of a jackknife free-response receiver operating characteristic (JAFROC) analysis method. Materials and Methods Twenty pairs of successive whole-body bone scans (72 consented interval changes) and their temporal subtraction images were used for an observer performance study. Our institutional review board approved the use of this database and the participation of radiologists in this study. In the first session of the observer study, without temporal subtraction images, the previous and current images were shown to five radiologists independently for their marking of the locations on current images and confidence ratings on potential interval changes from previous images. In the second session, temporal subtraction images were shown together with the modified previous and current images. JAFROC analysis was used for assessing the statistical significance of differences between radiologists’ performance without and with temporal subtraction images. Results The average sensitivity for detecting interval changes was improved from 58.6% to 73.2% at a false-positive rate of two per case by use of temporal subtraction images, and the difference was statistically significant by use of JAFROC analysis ( P = .035). In addition, the mean reading time per case was reduced considerably from 134 seconds to 91 seconds ( P Conclusions Temporal subtraction imaging for successive whole-body bone scans has the potential greatly to assist radiologists by increasing both their accuracy and productivity.

Whole-body metabolic tumor volume (MTVWB) has been shown of prognostic value for non-small cell lung cancer (NSCLC) beyond that of TNM stage, age, gender, performance status, and treatment selection. The current TNM staging system does not incorporate tumor volumetric information. We propose a new PET/CT volumetric prognostic (PVP) index that combines the prognostic value of MTVWB and TNM stage.Based on 328 consecutive NSCLC patients with a baseline PET/CT scan before treatment, from which MTVWB was measured semi-automatically, we estimated hazard ratios (HRs) for ln(MTVWB) and TNM stage from a Cox proportional hazard regression model that consisted of only ln(MTVWB) and TNM stage as prognostic variables of overall survival. We used the regression coefficients, which gave rise to the HRs, as weights to formulate the PET/CT volumetric prognostic (PVP) index. We also compared the prognostic value of the PVP index against that of TNM stage alone and ln(MTVWB) alone with univariate and multivariate survival analyses and C-statistics.Univariate analysis C-statistic for the PVP index (C=0.71) was statistically significantly greater than those for TNM stage alone (C=0.67, p0.01) and for ln(MTVWB) alone (C=0.69, p=0.033). Multivariate analyses showed that the PVP index yielded significantly greater discriminatory power (C=0.74) than similar models based on either TNM stage (C=0.72, p0.01) or ln(MTVWB) (C=0.73, p0.01). Lower values of the PVP index were associated with significantly better overall survival (adjusted HR=2.70, 95%CI [2.16, 3.37]).The PVP index provides a practical means for clinicians to combine the prognostic value of MTVWB and TNM stage and offers significantly better prognostic accuracy for overall survival of NSCLC patients than the current TNM staging system or metabolic tumor burden alone.

r Abstract: Functional magnetic resonance imaging was used to identify the neural correlates of Chinese character and word reading. The Chinese stimuli were presented visually, one at a time. Subjects covertly generated a word that was semantically related to each stimulus. Three sorts of Chinese items were used: single characters having precise meanings, single characters having vague meanings, and two-character Chinese words. The results indicated that reading Chinese is characterized by extensive activity of the neural systems, with strong left lateralization of frontal (BAs 9 and 47) and temporal (BA 37) cortices and right lateralization of visual systems (BAs 17-19), parietal lobe (BA 3), and cerebellum. The location of peak activation in the left frontal regions coincided nearly completely both for vague- and precise- meaning characters as well as for two-character words, without dissociation in laterality patterns. In addition, left frontal activations were modulated by the ease of semantic retrieval. The present results constitute a challenge to the deeply ingrained belief that activations in reading single characters are right lateralized, whereas activations in reading two-character words are left lateralized. Hum. Brain Mapping 10:16 -27, 2000. © 2000 Wiley-Liss, Inc.

The hypothalamus plays a central role in the regulation of energy intake and feeding behavior. However, the presence of a functional abnormality in the hypothalamus in humans that may be related to excess energy intake and obesity has yet to be demonstrated in vivo. We, therefore, used functional magnetic resonance imaging (fMRI) to monitor hypothalamic function after oral glucose intake. The 10 obese (34 +/- 2 years of age, BMI 34.2 +/- 1.3 kg/m2) and 10 lean (32 +/- 4 years of age, BMI 22.0 +/- 0.9 kg/m2) subjects with normal glucose tolerance ingested 75 g of glucose while a midsagittal slice through the hypothalamus was continuously imaged for 50 min using a conventional T2*-weighted gradient-echo pulse sequence. After glucose ingestion, lean subjects demonstrated an inhibition of the fMRI signal in the areas corresponding to the paraventricular and ventromedial nuclei. In obese subjects, this inhibitory response was markedly attenuated (4.8 +/- 1.3 vs. 7.0 +/- 0.6% inhibition, P < 0.05) and delayed (9.4 +/- 0.5 vs. 6.4 +/- 0.5 min, P < 0.05) compared with that observed in lean subjects. The time taken to reach the maximum inhibitory response correlated with the fasting plasma glucose (r = 0.75, P < 0.001) and insulin (r = 0.47, P < 0.05) concentrations in both lean and obese subjects. These results demonstrate in vivo, for the first time, the existence of differential hypothalamic function in lean and obese humans that may be secondary to obesity.

Many tasks require rapid and fine-tuned adjustment of motor performance based on incoming sensory information. This process of sensorimotor adaptation engages two parallel subcortico–cortical neural circuits, involving the cerebellum and basal ganglia, respectively1,2,3,4,5,6,7,8,9,10. How these distributed circuits are functionally coordinated has not been shown in humans. The cerebellum and basal ganglia show very similar convergence of input–output organization11,12, which presents an ideal neuroimaging model for the study of parallel processing at a systems level13. Here we used functional magnetic resonance imaging to measure the temporal coherence of brain activity during a tactile discrimination task. We found that, whereas the prefrontal cortex maintained a high level of activation, output activities in the cerebellum and basal ganglia showed different phasic patterns. Moreover, cerebellar activity significantly correlated with the activity of the supplementary motor area but not with that of the primary motor cortex; in contrast, basal ganglia activity was more strongly associated with the activity of the primary motor cortex than with that of the supplementary motor area. These results demonstrate temporally partitioned activity in the cerebellum and basal ganglia, implicating functional independence in the parallel subcortical outputs. This further supports the idea of task-related dynamic reconfiguration of large-scale neural networks14,15.

Background Radiolabeled metaiodobenzylguanidine (MIBG) is sensitive and specific for detecting neuroblastoma. The extent of MIBG-avid disease is assessed using Curie scores. Although Curie scoring is prognostic in patients with high-risk neuroblastoma, there is no standardized method to assess the response of specific sites of disease over time. The goal of this study was to develop approaches for Curie scoring to facilitate the calculation of scores and comparison of specific sites on serial scans. Procedure We designed three semiautomated methods for determining Curie scores, each with increasing degrees of computer assistance. Method A was based on visual assessment and tallying of MIBG-avid lesions. For method B, scores were tabulated from a schematic that associated anatomic regions to MIBG-positive lesions. For method C, an anatomic mesh was used to mark MIBG-positive lesions with automatic assignment and tallying of scores. Five imaging physicians experienced in MIBG interpretation scored 38 scans using each method, and the feasibility and utility of the methods were assessed using surveys. Results There was good reliability between methods and observers. The user-interface methods required 57 to 110 seconds longer than the visual method. Imaging physicians indicated that it was useful that methods B and C enabled tracking of lesions. Imaging physicians preferred method B to method C because of its efficiency. Conclusions We demonstrate the feasibility of semiautomated approaches for Curie score calculation. Although more time was needed for strategies B and C, the ability to track and document individual MIBG-positive lesions over time is a strength of these methods.

To determine whether whole-body metabolic tumor burden, measured as either metabolic tumor volume (MTVWB) or total lesion glycolysis (TLGWB), using FDG-PET/CT is an independent prognostic marker in non-small cell lung cancer (NSCLC).328 patients with histologically proven NSCLC were identified for this retrospective analysis. This study was approved by our Institutional Review Board. All patients underwent baseline (18)F-FDG-PET/CT scan imaging before therapy. The MTVWB, TLGWB, maximum standardized uptake value (SUVmaxWB) and mean standardized uptake value (SUVmeanWB) of tumors throughout the whole body were measured from FDG-PET images with semi-automated 3D contouring software.In univariate analysis, there was a statistically significant association of overall survival (OS) with the MTVWB (hazard ratio (HR) = 1.62, p 0.001), TLGWB (HR = 1.47, p 0.001). The patients with a MTVWB ≤ median of 65.7 ml and TLGWB ≤ median of 205.11 SUVmean * ml had a median OS of 41.1 and 35.4 months compared with 9.5 and 9.7 months for those with a MTVWB 65.7 ml and TLGWB 205.11 SUVmean * ml, respectively. From a series of multivariate Cox regression models, the MTVWB and TLGWB were significantly better than SUVmaxWB and SUVmeanWB at prognostication and significantly associated with patients' OS with HRs of 1.50 (p 0.001) and 1.42 (p 0.001), respectively, after adjustment for patient's age, gender and treatment intent as well as the tumor SUVmaxWB, histology and stage.MTVWB and TLGWB as metabolic tumor burden measurements in (18)F-FDG-PET/CT are independent prognostic markers and are significantly better than SUVmaxWB and SUVmeanWB at prognostication.

The utility of magnetic resonance imaging (MRI) in the diagnosis of acute cholecystitis was evaluated in 72 consecutive individuals (5 healthy, 13 with chronic cholecystitis and silent gallbladder stones, 43 without biliary or diffuse liver disease, and 11 with acute cholecystitis and gallbladder stones) with a 0.5-T superconducting unit. On the T1-weighted (500/20) and less T1-weighted axial spin-echo images (620/25), the liver/gallbladder signal intensity ratio (mean +/- SD) was 2.5 +/- 0.51 (n = 5) and 1.8 +/- 0.29 (n = 8) in acute cholecystitis; 0.9 +/- 0.42 (n = 6) and 1.0 +/- 0.29 (n = 9) in chronic cholecystitis; and 0.9 +/- 0.14 (n = 5) and 0.8 +/- 0.19 (n = 43) in normal gallbladder, respectively. Our results indicate that the liver/gallbladder signal intensity ratio on the T1-weighted image may be a simple and reliable indicator for the diagnosis of acute cholecystitis; we suggest further investigation to confirm these results.

To assess the prognostic value of metabolic tumor burden as measured with metabolic tumor volume (MTV) and total lesion glycolysis (TLG) on 2-deoxy-2-((18)F)fluoro-D-glucose ((18)F-FDG) positron emission tomography (PET)/computed tomography (CT), independent of current Union Internacional Contra la Cancrum/American Joint Committee on Cancer tumor, node, and metastasis (TNM) stage; in comparison with that of standardized uptake value (SUV) in surgical patients with non-small-cell lung cancer (NSCLC).This study retrospectively reviewed 104 consecutive surgical patients (47 males, 57 females, median age at PET/CT scan of 67.92 years) with diagnosed stage I to IV NSCLC who had baseline (18)F-FDG PET/CT scans. The (18)F-FDG PET/CT scans were performed in accordance with National Cancer Institute guidelines. The MTV of tumors in the whole body (MTV(WB)), TLG of tumors in the whole body (TLG(WB)), the maximum standardized uptake value of tumors in the whole body (SUV(maxWB)) as well as the mean standardized uptake value of tumor in the whole body (SUV(meanWB)) were measured. The median follow-up among 67 survivors was 42.07 months from the PET/CT (range 2.82-80.95 months). Statistical methods included Kaplan-Meier curves, Cox regression, and C-statistics. The interobserver variability of SUV(maxWB), SUV(meanWB), MTV(WB), and TLG(WB) between two observers was analyzed using concordance correlation coefficients (CCCs).The interobserver variability of SUV(maxWB), SUV(meanWB), MTV(WB) and TLG(WB) was very low with CCCs greater than 0.882. There was a statistically significant association of stage with overall survival (OS). The hazard ratio (HR) of stage III and stage IV as compared with stage I was 3.60 (P = .001) and 4.00 (P = .013), respectively. The MTV(WB) was significantly associated with OS with a HR for 1-unit increase of ln(MTV(WB)) of 1.40/1.32 (P = .004/.039), before/after adjusting for stage and other prognostic factors including chemoradiation therapy, and surgical procedure, respectively. TLG(WB) had a statistically significant association with OS before and after adjusting for stage and the other prognostic factors. The HR for 1-unit increase in ln(TLG(WB)) was 1.26 (P = .011) and 1.25 (P = .031), before and after the adjustment, respectively. Subjects with conditions that led to pneumonectomy (HR = 2.82, P = .035) or segmental resection (HR = 3.44, P = .044) had significantly worse survival than those needing lobectomy. There was no statistically significant association between OS and age, gender, tumor histology, ln(SUV(maxWB)), and ln(SUV(meanWB)) (all P.05). There were 37 deaths during follow-up.Baseline whole-body metabolic tumor burden as measured with MTV(WB) and TLG(WB) on FDG PET is a prognostic measure independent of clinical stage and other prognostic factors including chemoradiation therapy and surgical procedure with low interobserver variability and may be used to further risk stratify surgical patients with NSCLC. This study also suggests that MTV and TLG are better prognostic measures than SUV(max) and SUV(mean). These results will need to be validated in larger cohorts in a prospective study.

Rationale and Objectives Stage IV non–small-cell lung cancer (NSCLC) consists of a heterogeneous group of patients with different prognoses. We assessed the prognostic value of baseline whole body tumor burden as measured by metabolic tumor volume (MTV), total lesion glycolysis (TLG), and standardized uptake values (SUV max and SUV mean ) of all tumors in nonsurgical patients with Stage IV NSCLC. Materials and Methods Ninety-two consecutive patients with newly diagnosed Stage IV NSCLC who had a pretreatment F-18 fludeoxyglucose positron emission tomography/computed tomography scan were retrospectively reviewed. The MTV, TLG, SUV mean , and SUV max of whole-body (WB) tumors were measured with the MIMvista workstation with manual adjustment. Results There was a statistically significant association between overall survival (OS) and ln(MTV)/ln(TLG) at the level of WB tumor burden (MTV WB ) and of primary tumor (MTV T ). The hazard ratio (HR) for a 1-unit increase of ln(MTV WB ) and ln(MTV T ) before and after adjusting for age and gender was 1.48/1.48 (both P P = .006, .007), respectively. The HR for a 1-unit increase of ln(TLG WB ) and ln(TLG T ) before and after adjusting for age and gender was 1.37/1.37 (both P = .001) and 1.19/1.19 ( P = .001, .017), respectively. There was no statistically significant association between OS and ln(SUV max ) and ln(SUV mean ) at WB tumor burden, primary tumor, nodal metastasis, or distant metastasis ( P > .05). There was low interobserver variability between two radiologists with concordance correlation coefficients of 0.90 for ln(MTV WB ) and greater than 0.90 for SUV maxWB , SUV meanWB , and ln(TLG WB ). Conclusion Baseline WB metabolic tumor burden, as measured with MTV and TLG, is a prognostic measurement in patients within Stage IV NSCLC with low interobserver variability. This study also suggests pretreatment MTV and TLG measurements may be used to further stratify patients with Stage IV NSCLC and are better prognostic measures than SUV max and SUV mean measurements.

Six patients with hepatic laceration underwent magnetic resonance imaging (MRI) at 0.5T. Acute hepatic laceration was slightly hypointense on T1-weighted spin-echo (SE) image, and hyperintense on T2- and proton-weighted SE images. Subacute laceration was heterogeneously intense on T1-weighted image and hyperintense on T2- and proton-weighted images. Consistent changes in signal intensity of postoperative hepatic laceration were observed. On T1-weighted image, the signal intensity at first increased and then decreased from periphery to the center. On the T2- and proton-weighted images, the laceration was uniformly hyperintense relative to the liver prior to the appearance and growth of a hypointense ring at its periphery. The appearance of the above changes in signal intensity was also observed in postoperative recurrent hemorrhage. The postoperative biloma had none of the above changes in signal intensity. Our cases show that MRI is effective in the evaluation of hepatic laceration and in the assessment of the course of healing after operation.

Background:18F-fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET) imaging has been shown to be an accurate method for diagnosing pulmonary lesions, and the standardized uptake value (SUV) has been shown to be useful in differentiating benign from malignant lesions. Purpose: To survey the interobserver variability of SUVmax and SUVmean measurements on 18F-FDG PET/CT scans and compare them with tumor size measurements on diagnostic CT scans in the same group of patients with focal pulmonary lesions. Material and Methods: Forty-three pulmonary nodules were measured on both 18F-FDG PET/CT and diagnostic chest CT examinations. Four independent readers measured the SUVmax and SUVmean of the 18F-FDG PET images, and the unidimensional nodule size of the diagnostic CT scans (UDCT) in all nodules. The region of interest (ROI) for the SUV measurements was drawn manually around each tumor on all consecutive slices that contained the nodule. The interobserver reliability and variability, represented by the intraclass correlation coefficient (ICC) and coefficient of variation (COV), respectively, were compared among the three parameters. The correlation between the SUVmax and SUVmean was also analyzed. Results: There was 100% agreement in the SUVmax measurements among the 4 readers in the 43 pulmonary tumors. The ICCs for the SUVmax, SUVmean, and UDCT by the four readers were 1.00, 0.97, and 0.97, respectively. The root-mean-square values of the COVs for the SUVmax, SUVmean, and UDCT by the four readers were 0%, 13.56%, and 11.03%, respectively. There was a high correlation observed between the SUVmax and SUVmean (Pearson's r=0.958; P Conclusion: This study has shown that the SUVmax of lung nodules can be calculated without any interobserver variation. These findings indicate that SUVmax is a more valuable parameter than the SUVmean or UDCT for the evaluation of therapeutic effects of chemotherapy or radiation therapy on serial studies.

The authors report the fluorodeoxyglucose (FDG)-positron emission tomography(PET)/computed tomography (CT) findings of a rare case of growth hormone-secreting pituitary carcinoma with multiple metastatic lesions to the skeleton. A 31-year-old male had presented with acromegaly and had received transsphenoidal resection of a pituitary tumor and adjuvant radiotherapy. However, the tumor recurred with local invasions and the patient underwent more resections and adjuvant chemotherapy. Several months later, the patient developed rising levels of insulin-like growth factor 1 and whole-body FDG-PET/CT scanning revealed multiple hypermetabolic lesions throughout the skeleton compatible with metastasis.

BACKGROUND AND PURPOSE: Although the prevalence of pineal cysts in autopsy series has been reported as being between 25% and 40%, MR studies have documented their frequency to range between 1.5% and 10.8%. The purpose of this high-resolution brain MR imaging study at 1.9T was to determine the prevalence of pineal cysts in healthy adults. MATERIALS AND METHODS: Brain MR images of 100 healthy young volunteers were randomly selected from our International Consortium for Brain Mapping project data base. Cysts were detected as circular areas of isointensity relative to CSF on both 3D gradient-echo T1-weighted and 2D fast spin-echo T2-weighted images. The inner diameters of all visualized pineal cysts were measured, and a criterion of 2.0 mm of the largest inner cross-sectional diameter was used to categorize cysts as being either small cystic changes (2.0-mm diameter). RESULTS: Twenty-three percent (23/100) of the volunteers had pineal cysts with a mean largest inner cross-sectional diameter of 4.3 mm (range, 2–14 mm); 13% (13/100) demonstrated cystic changes involving the pineal gland with the largest inner cross-sectional diameter of less than 2.0 mm. There was a slight female predominance. Two subjects with long-term follow-up scans showed no symptoms or changes in the size of their pineal cysts. CONCLUSION: On high-resolution MR imaging, the prevalence of pineal cysts was 23% in our healthy group of adults, which is consistent with previous autopsy studies. Long-term follow-up studies of 2 cases demonstrated the stability of the cysts.

Bone scintigraphy is the most frequent examination among various diagnostic nuclear medicine procedures. It is a well-established imaging modality for the diagnosis of osseous metastasis and for monitoring osseous tumor response to chemotherapy and radiation therapy. Although the sensitivity of bone scan examinations for detection of bone abnormalities has been considered to be relatively high, it is time consuming to identify multiple lesions such as bone metastases of prostate and breast cancers. In addition, it is very difficult to detect subtle interval changes between two successive abnormal bone scans, because of variations in patient conditions, the accumulation of radioisotopes during each examination, and the image quality of gamma cameras. Therefore, we developed a new computer-aided diagnostic (CAD) scheme for the detection of interval changes in successive whole-body bone scans by use of a temporal subtraction image which was obtained with a nonlinear image-warping technique. We carried out 58 pairs of successive bone scans in which each scan included both posterior and anterior views. We determined 107 "gold-standard" interval changes among the 58 pairs based on the consensus of three radiologists. Our computerized scheme consisted of seven steps, i.e., initial image density normalization on each image, image matching for the paired images, temporal subtraction by use of the nonlinear image-warping technique, initial detection of interval changes by use of temporal-subtraction images, image feature extraction of candidates of interval changes, rule-based tests by use of 16 image features for removing some false positives, and display of the computer output for identified interval changes. One hundred seven gold standard interval changes included 71 hot lesions (uptake was increased compared with the previous scan, or there was new uptake in the current scan) and 36 cold lesions (uptake was decreased or disappeared) for anterior and posterior views. The overall sensitivity in the detection of interval changes, including both hot and cold lesions evaluated by use of the resubstitution and the leave-one-case-out methods, were 95.3%, with 5.97 false positives per view, and 83.2% with 6.02, respectively. The temporal subtraction image for successive whole-body bone scans has the potential to enhance the interval changes between two images, which also can be quantified. Furthermore, the CAD scheme for the detection of interval changes by use of temporal subtraction images would be useful in assisting radiologists' interpretation on successive bone scan images.

Our objective was to develop and evaluate 3 semiautomatic computer-aided diagnostic (CAD) schemes for distinguishing between benign and malignant pulmonary nodules by use of features extracted from CT, 18F-FDG PET, and both CT and 18F-FDG PET.We retrospectively collected 92 consecutive cases of pulmonary nodules (3 cm) in patients who underwent both thoracic CT and whole-body PET/CT. Forty-two of the nodules were malignant and 50 benign, as confirmed by pathologic examination and clinical follow-up. The interval between CT and PET was less than 1 mo. Four clinical parameters, including patient age, sex, smoking status, and history of previous malignancy, were used for the CAD schemes. Sixteen CT features based on size, shape, margin, and internal structure of nodules were independently rated subjectively by 2 chest radiologists. Four PET features were viewed on a PET/CT workstation. CAD schemes based on clinical parameters together with CT features, PET features, and both CT and PET features were then used to differentiate benign from malignant nodules. Finally, the output from the CAD schemes was evaluated by use of receiver-operating-characteristic analysis.When we used clinical parameters and CT features as input units (CAD scheme 1), the area under the receiver-operating-characteristic curve (A(z) value) of the CAD scheme was 0.83. When we used clinical parameters and PET features as input units (CAD scheme 2), the A(z) value for the computer output was 0.91. However, when we used all data as input units (CAD scheme 3), the A(z) value for the computer output was 0.95. The performance of CAD scheme 3 was better than that of CAD scheme 1 or 2. A statistically significant difference existed between the A(z) values of CAD schemes 3 and 2 (P = 0.037) and between those of CAD schemes 3 and 1 (P = 0.015).Our CAD scheme based on both PET and CT was better able to differentiate benign from malignant pulmonary nodules than were the CAD schemes based on PET alone and CT alone.

The magnetic resonance imaging (MRI) differential diagnosis of intrahepatic biloma from intrahepatic subacute hematoma has been reported in two cases. The biloma was heterogenously intense on T1-weighted images and homogenously hyperintense on T2-weighted images. The hematoma was hyperintense on the both T1- and T2-weighted MR images. The clinical significance of this MRI difference is that intrahepatic biloma needs drainage, whereas intrahepatic hematoma can heal spontaneously.

The diagnosis of hemobilia is difficult. Computed tomography and ultrasonography generally yield only contributory information about blood or clots in the gallbladder but cannot demonstrate bleeding. This case report shows that magnetic resonance imaging (MRI) can not only demonstrate traumatic hemobilia in the gallbladder, and its origin, but can also determine active bleeding from liver lacerations and hematoma.

Comparative functional neuroimaging studies using the block design paradigm have previously demonstrated that there are no significant differences in the location of areas of cerebral activation when native Chinese speakers independently process single words or sentences in both the Chinese (first) and English (second) languages. While it has also been documented that significant domains of brain response include the inferior to middle left frontal lobe, the latency, amplitude and duration of the associated hemodynamic changes during isolated neural processing of Chinese and English languages still remain unknown. The aim of this study, therefore, was to examine the characteristics of the hemodynamic alterations in the above-mentioned regions with event-related functional MRI (ER-fMRI) when native Chinese speakers performed verb generation tasks in both the Chinese (first) and English (second) languages. Our results demonstrate the presence of a similar neural activity-induced hemodynamic response in the inferior to middle left frontal lobe during both tasks. Further, there were also no statistically significant differences among the variables that described the hemodynamic response curves. These findings strongly imply that the underlying neural mechanism for Chinese (first) and English (second) language processing may be similar in native Chinese speakers.

A functional MRI study compared activation in the red nucleus to that in the lateral cerebellar dentate nucleus during passive and active tactile discrimination tasks. The study pursued recent neuroimaging results suggesting that the cerebellum may be more associated with sensory processing than with the control of movement for its own sake. Because the red nucleus interacts closely with the cerebellum, the possibility was examined that activity in red nucleus might also be driven by the requirement for tactile sensory processing with the fingers rather than by finger movement alone. The red and dentate nuclei were about 300% more active (a combination of activation areas and intensities) during passive (non‐motor) tactile stimulation when discrimination was required than when it was not. Thus, the red nucleus was activated by purely sensory stimuli even in the absence of the opportunity to coordinate finger movements or to use the sensory cues to guide movement. The red and dentate nuclei were about 70% more active during active tactile tasks when discrimination was required than when it was not (i.e., for simple finger movements alone). Thus, the red nucleus was most active when the fingers were being used for tactile sensory discrimination. In both the passive and active tactile tasks, the observed activation had a contralateralized pattern, with stronger activation in the left red nucleus and right dentate nucleus. Significant covariation was observed between activity in the red nucleus and the contralateral dentate during the discrimination tasks and no significant correlation between the red nucleus and the contralateral dentate activity was detected during the two non‐discrimination tasks. The observed interregional covariance and contralateralized activation patterns suggest strong functional connectivity during tactile discrimination tasks. Overall, the pattern of findings suggests that the activity in the red nucleus, as in the lateral cerebellum, is more driven by the requirements for sensory processing than by motor coordination per se. Hum. Brain Mapping 10:147–159, 2000. © 2000 Wiley‐Liss, Inc.

Event-related (ER) fMRI has evoked great interest due to the ability to depict the dynamic features of human brain function during various cognitive tasks. Thus far, all cognitive ER-fMRI studies have been based on blood oxygenation level-dependent (BOLD) contrast techniques. Compared with BOLD-based fMRI techniques, perfusion-based fMRI is able to localize the region of neuronal activity more accurately. This report demonstrates, for the first time, the detection of the brain response to a cognitive task using high temporal resolution perfusion-based ER-fMRI. An English verb generation task was used in this study. Results show that perfusion-based ER-fMRI accurately depicts the activation in Broca's area. Average changes in regional relative cerebral blood flow reached a maximum value of 30.7% at approximately 6.5 s after the start of stimulation and returned to 10% of the maximum value at approximately 12.8 s. Our results show that perfusion-based ER-fMRI is a useful tool for cognitive neuroscience studies, providing comparable temporal resolution and better localization of brain function than BOLD ER-fMRI.