Robert Kozarski

Assessment of Primary Colorectal Cancer Heterogeneity by Using Whole-Tumor Texture Analysis : Contrast-enhanced CT Texture as a Biomarker of 5-year Survival

PURPOSE To determine if computed tomographic (CT) texture features of primary colorectal cancer are related to 5-year overall survival rate. MATERIALS AND METHODS Institutional review board waiver was obtained for this retrospective analysis. Texture features of the entire primary tumor were assessed with contrast material-enhanced staging CT studies obtained in 57 patients as part of an ethically approved study and by using proprietary software. Entropy, uniformity, kurtosis, skewness, and standard deviation of the pixel distribution histogram were derived from CT images without filtration and with filter values corresponding to fine (1.0), medium (1.5, 2.0), and coarse (2.5) textures. Patients were followed up until death and were censored at 5 years if they were still alive. Kaplan-Meier analysis was performed to determine the relationship, if any, between CT texture and 5-year overall survival rate. The Cox proportional hazards model was used to assess independence of texture parameters from stage. RESULTS Follow-up data were available for 55 of 57 patients. There were eight stage I, 19 stage II, 17 stage III, and 11 stage IV cancers. Fine-texture feature Kaplan-Meier survival plots for entropy, uniformity, kurtosis, skewness, and standard deviation of the pixel distribution histogram were significantly different for tumors above and below each respective threshold receiver operating characteristic (ROC) curve optimal cutoff value (P = .001, P = .018, P = .032, P = .008, and P = .001, respectively), with poorer prognosis for ROC optimal values (a) less than 7.89 for entropy, (b) at least 0.01 for uniformity, (c) less than 2.48 for kurtosis, (d) at least -0.38 for skewness, and (e) less than 61.83 for standard deviation. Multivariate Cox proportional hazards regression analysis showed that each parameter was independent from the stage predictor of overall survival rate (P = .001, P = .009, P = .006, P = .02, and P = .001, respectively). CONCLUSION Fine-texture features are associated with poorer 5-year overall survival rate in patients with primary colorectal cancer. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120254/-/DC1.

Assessment of tumor heterogeneity by CT texture analysis: Can the largest cross-sectional area be used as an alternative to whole tumor analysis?

OBJECTIVE To determine if there is a difference between contrast enhanced CT texture features from the largest cross-sectional area versus the whole tumor, and its effect on clinical outcome prediction. METHODS Entropy (E) and uniformity (U) were derived for different filter values (1.0-2.5: fine to coarse textures) for the largest primary tumor cross-sectional area and the whole tumor of the staging contrast enhanced CT in 55 patients with primary colorectal cancer. Parameters were compared using non-parametric Wilcoxon test. Kaplan-Meier analysis was performed to determine the relationship between CT texture and 5-year overall survival. RESULTS E was higher and U lower for the whole tumor indicating greater heterogeneity at all filter levels (1.0-2.5): median (range) for E and U for whole tumor versus largest cross-sectional area of 7.89 (7.43-8.31) versus 7.62 (6.94-8.08) and 0.005 (0.004-0.01) versus 0.006 (0.005-0.01) for filter 1.0; 7.88 (7.22-8.48) versus 7.54 (6.86-8.1) and 0.005 (0.003-0.01) versus 0.007 (0.004-0.01) for filter 1.5; 7.88 (7.17-8.54) versus 7.48 (5.84-8.25) and 0.005 (0.003-0.01) versus 0.007 (0.004-0.02) for filter 2.0; and 7.83 (7.03-8.57) versus 7.42 (5.19-8.26) and 0.005 (0.003-0.01) versus 0.006 (0.004-0.03) for filter 2.5 respectively (p ≤ 0.001). Kaplan-Meier analysis demonstrated better separation of E and U for whole tumor analysis for 5-year overall survival. CONCLUSION Whole tumor analysis appears more representative of tumor heterogeneity.

Use of Dynamic Contrast-enhanced MR Imaging to Predict Survival in Patients with Primary Breast Cancer Undergoing Neoadjuvant Chemotherapy

PURPOSE To investigate whether early changes in vascular parameters determined with dynamic contrast material-enhanced magnetic resonance (MR) imaging after two cycles of neoadjuvant chemotherapy (NAC) are predictive of disease-free and overall survival in primary breast cancer. MATERIALS AND METHODS Institutional ethics approval and informed consent were obtained. Patients with primary breast cancer (median age, 45 years; age range, 22-70 years) recruited from January 2001 to September 2008 underwent dynamic contrast-enhanced MR imaging before and after two cycles of NAC. Quantitative and semiquantitative kinetic parameters were calculated, including the volume transfer constant (K(trans)) and the initial area under the gadolinium concentration-time curve over 60 seconds (IAUGC(60)). Cut points optimized to the receiver operating characteristic curve were used to dichotomize MR imaging data for Kaplan-Meier survival analysis. MR imaging parameters and known prognostic indicators in primary breast cancer were correlated with disease-free and overall survival by using the Cox proportional hazards model for univariate and multivariate analyses. RESULTS MR imaging was performed before (n = 62) and after (n = 58) two cycles of NAC. The median follow-up time was 43.9 months for disease-free survival and 60.3 months for overall survival. There were 28 recurrences; 26 patients had distant metastases (two had additional local recurrence) and two had local recurrence only. There were 20 deaths, all of which were related to breast cancer. At univariate analysis, progesterone receptor status, the type of surgery performed, higher posttreatment K(trans) (P = .048), and larger posttreatment IAUGC(60) (P = .035) were significant predictors of worse disease-free survival. At multivariate analysis, progesterone receptor status (P = .002) and mean transit time (P = .025) were significant predictors of disease-free survival. Univariate analysis showed that clinical tumor stage (P = .005), progesterone receptor status (P = .025), and type of surgery performed (P = .017) were significant predictors of overall survival. Higher posttreatment K(trans) (P = .043), larger IAUGC(60) (P = .029), and larger tumor size at posttreatment MR imaging were predictive of worse overall survival (P = .018). Of these variables, K(trans) remained an independent indicator of overall survival (P = .038). CONCLUSION Higher posttreatment tumor vascularization as depicted with dynamic contrast-enhanced MR imaging may be associated with higher recurrence and lower survival rates. Dynamic contrast-enhanced MR imaging parameters, in conjunction with traditional prognostic factors, have the potential to be prognostic biomarkers for disease-free and overall survival in primary breast cancer.

Primary Esophageal Cancer: Heterogeneity as Potential Prognostic Biomarker in Patients Treated with Definitive Chemotherapy and Radiation Therapy

PURPOSE To determine the association between tumor heterogeneity, morphologic tumor response, and overall survival in primary esophageal cancer treated with chemotherapy and radiation therapy (CRT). MATERIALS AND METHODS After an institutional review board waiver was obtained, contrast material-enhanced computed tomographic (CT) studies in 36 patients with stage T2 or greater esophageal tumors who underwent contrast-enhanced CT before and after CRT between 2005 and 2008 were analyzed in terms of whole-tumor texture, with quantification of entropy, uniformity, mean gray-level intensity, kurtosis, standard deviation of the histogram, and skewness for fine to coarse textures (filters 1.0-2.5, respectively). The association between texture parameters and survival time was assessed by using Kaplan-Meier analysis and a Cox proportional hazards model. Survival models involving texture parameters and combinations of texture and morphologic response assessment were compared with morphologic assessment alone by means of receiver operating characteristic (ROC) analysis. RESULTS Posttreatment medium entropy of less than 7.356 (median overall survival, 33.2 vs 11.7 months; P = .0002), coarse entropy of less than 7.116 (median overall survival, 33.2 vs 11.7 months; P = .0002), and medium uniformity of 0.007 or greater (median overall survival, 33.2 vs 11.7 months; P = .0002) were associated with improved survival time. These remained significant prognostic factors after adjustment for stage and age: entropy (filter 2.0: hazard ratio [HR] = 5.038, P = .0004; filter 2.5: HR = 5.038, P = .0004) and uniformity (HR = 0.199, P = .0004). Survival models that included a combination of pretreatment entropy and uniformity with maximal wall thickness assessment, respectively, performed better than morphologic assessment alone (area under the ROC curve, 0.767 vs 0.487 [P = .00005] and 0.802 vs 0.487 [P = .0003]). CONCLUSION Posttreatment texture parameters are associated with survival time, and the combination of pretreatment texture parameters and maximal wall thickness performed better in survival models than morphologic tumor response alone.

Primary Esophageal Cancer Heterogeneity as a Potential Prognostic Biomarker in Patients Treated with Definitive Chemoradiation

PURPOSE To determine the association between tumor heterogeneity, morphologic tumor response, and overall survival in primary esophageal cancer treated with chemotherapy and radiation therapy (CRT). MATERIALS AND METHODS After an institutional review board waiver was obtained, contrast material-enhanced computed tomographic (CT) studies in 36 patients with stage T2 or greater esophageal tumors who underwent contrast-enhanced CT before and after CRT between 2005 and 2008 were analyzed in terms of whole-tumor texture, with quantification of entropy, uniformity, mean gray-level intensity, kurtosis, standard deviation of the histogram, and skewness for fine to coarse textures (filters 1.0-2.5, respectively). The association between texture parameters and survival time was assessed by using Kaplan-Meier analysis and a Cox proportional hazards model. Survival models involving texture parameters and combinations of texture and morphologic response assessment were compared with morphologic assessment alone by means of receiver operating characteristic (ROC) analysis. RESULTS Posttreatment medium entropy of less than 7.356 (median overall survival, 33.2 vs 11.7 months; P = .0002), coarse entropy of less than 7.116 (median overall survival, 33.2 vs 11.7 months; P = .0002), and medium uniformity of 0.007 or greater (median overall survival, 33.2 vs 11.7 months; P = .0002) were associated with improved survival time. These remained significant prognostic factors after adjustment for stage and age: entropy (filter 2.0: hazard ratio [HR] = 5.038, P = .0004; filter 2.5: HR = 5.038, P = .0004) and uniformity (HR = 0.199, P = .0004). Survival models that included a combination of pretreatment entropy and uniformity with maximal wall thickness assessment, respectively, performed better than morphologic assessment alone (area under the ROC curve, 0.767 vs 0.487 [P = .00005] and 0.802 vs 0.487 [P = .0003]). CONCLUSION Posttreatment texture parameters are associated with survival time, and the combination of pretreatment texture parameters and maximal wall thickness performed better in survival models than morphologic tumor response alone.

Operable Non–Small Cell Lung Cancer: Correlation of Volumetric Helical Dynamic Contrast-enhanced CT Parameters with Immunohistochemical Markers of Tumor Hypoxia

PURPOSE To assess the relationship between helical dynamic contrast material-enhanced (DCE) computed tomographic (CT) parameters and immunohistochemical markers of hypoxia in patients with operable non-small cell lung cancer (NSCLC). MATERIALS AND METHODS After institutional review board approval was obtained, 20 prospective patients who were suspected of having NSCLC underwent whole-tumor DCE CT with kinetic modeling (Patlak analysis) 24 hours before scheduled surgery. Flow-extraction product (in milliliters per 100 milliliters per minute) and blood volume (in milliliters per 100 milliliters) were derived. After surgery, matched whole-tumor sections were stained for exogenous and endogenous markers of hypoxia (pimonidazole infused intravenously 24 hours before surgery, immediately after DCE CT; glucose transporter protein). Correlation between DCE CT parameters and immunohistochemical markers was assessed by using the Spearman rank correlation. DCE CT parameters and immunohistochemical markers were also compared according to pathologic subtype, grade, stage, and nodal status by using the Mann-Whitney test. P values less than .05 indicated a statistically significant difference. RESULT Fourteen patients with confirmed primary NSCLC underwent resection. There were negative correlations between blood volume and pimonidazole staining (r = -0.48, P = .004), and between flow-extraction product and glucose transporter protein expression (r = -0.50, P = .002). Flow-extraction product was significantly higher in adenocarcinomas than in squamous cell tumors (17.73 vs 11.46; P = .043). Glucose transporter protein expression was significantly lower for adenocarcinomas than for squamous tumors (14.07 vs 33.03; P < .001) and in node negative than in node positive tumors (15.63 vs 23.85; P = .005). CONCLUSION Blood volume and flow-extraction product derived at DCE CT correlated negatively with pimonidazole and glucose transporter protein expression, indicating the potential of these CT parameters as imaging biomarkers of hypoxia.

Children's, physical activity assessed with wrist- and hip-worn accelerometers

BACKGROUND Recently, triaxial raw acceleration accelerometers have become available from GENEActiv and ActiGraph; both are designed for wrist and hip wear. It is important to determine whether the output from these monitors is comparable with the wealth of data already collected from the hip-worn, epoch-based, uniaxial ActiGraph. PURPOSE This study aimed to assess the concurrent validity of measures of total activity and time spent at different activity intensities from the GENEActiv relative to the ActiGraph GT3X+. METHODS Fifty-eight children age 10-12 yr wore two accelerometers at the hip (ActiGraph GT3X+ and GENEActiv) and one at the wrist (GENEActiv) for 7 d. Wear time was matched for all monitors before analysis. RESULTS Mean daily accelerometer output, time spent sedentary, and time in moderate-to-vigorous physical activity (MVPA) from the hip- or wrist-worn GENEActiv were strongly correlated with the corresponding output from the hip-worn ActiGraph (r > 0.83, P < 0.001). However, less time was estimated to be sedentary and more time was estimated to be MVPA using the hip- or wrist-worn GENEActiv (Phillips cut points) than that when using the Evenson vertical axis cut points with the hip-worn ActiGraph. Output from the vertical axis ActiGraph cut points could be predicted with 95% limits of agreement, equating to 23%-28% and 33%-35% of the mean value, by the hip- and wrist-worn GENEActiv, respectively. CONCLUSIONS The assessment of childrens activity level, time spent sedentary, and time in MVPA estimated from the hip- or wrist-worn GENEActiv seems to be comparable with that of the uniaxial ActiGraph. On the basis of the strong linear correlations, ActiGraph output can be predicted from the hip- or wrist-worn GENEActiv for comparative purposes at the group level. However, because of relatively wide limits of agreement, individual-level comparisons are not recommended.

Impaired thrombolysis: a novel cardiovascular risk factor in end-stage renal disease

AIMS End-stage renal disease (ESRD) patients have an excess cardiovascular risk, above that predicted by traditional risk factor models. Prothrombotic status may contribute to this increased risk. Global thrombotic status assessment, including measurement of occlusion time (OT) and thrombolytic status, may identify vulnerable patients. Our aim was to assess overall thrombotic status in ESRD and relate this to cardiovascular risk. METHODS AND RESULTS Thrombotic and thrombolytic status of ESRD patients (n = 216) on haemodialysis was assessed using the Global Thrombosis Test. This novel, near-patient test measures the time required to form (OT) and time required to lyse (lysis time, LT) an occlusive platelet thrombus. Patients were followed-up for 276 ± 166 days for major adverse cardiovascular events (MACE, composite of cardiovascular death, non-fatal MI, or stroke). Peripheral arterial or arterio-venous fistula thrombosis was a secondary endpoint. Occlusion time was reduced (491 ± 177 vs. 378 ± 96 s, P < 0.001) and endogenous thrombolysis was impaired (LT median 1820 vs.1053 s, P < 0.001) in ESRD compared with normal subjects. LT ≥ 3000 s occurred in 42% of ESRD patients, and none of the controls. Impaired endogenous thrombolysis (LT ≥ 3000 s) was strongly associated MACE (HR = 4.25, 95% CI = 1.58-11.46, P = 0.004), non-fatal MI and stroke (HR = 14.28, 95% CI = 1.86-109.90, P = 0.01), and peripheral thrombosis (HR = 9.08, 95% CI = 2.08-39.75, P = 0.003). No association was found between OT and MACE. CONCLUSION Impaired endogenous thrombolysis is a novel risk factor in ESRD, strongly associated with cardiovascular events.

Assessment of changes in tumor heterogeneity following neoadjuvant chemotherapy in primary esophageal cancer

To assess the changes in computed tomography (CT) tumor heterogeneity following neoadjuvant chemotherapy in esophageal cancer. Thirty-one consecutive patients who received neoadjuvant chemotherapy for esophageal cancer were identified. Analysis of primary tumor heterogeneity (texture) was performed on staging and post-chemotherapy CT scans. Image texture parameters (mean grey-level intensity, entropy, uniformity, kurtosis, skewness, standard deviation of histogram) were derived for different levels of image filtration (0-2.5). Proportional changes in each parameter following treatment were obtained. Comparison between pathological tumor response and texture parameters was analyzed using Mann-Whitney U-test. The relationship between CT texture and overall survival) was estimated using the Kaplan-Meier method. Tumor texture became more homogeneous after treatment with a significant decrease in entropy and increase in uniformity (filter 1.0 and 2.5). Pretreatment (filter 1.5, P = 0.006) and posttreatment standard deviation of histogram (filter 1.0, P = 0.009) showed a borderline association with pathological tumor response. A proportional change in skewness <0.39 (filter 1.0) was associated with improved survival (median overall survival 36.1 vs. 11.1 months; P < 0.001). CT tumor heterogeneity decreased following neoadjuvant chemotherapy and has the potential to provide additional information in primary esophageal cancer.

Number of Days Required to Estimate Habitual Activity Using Wrist-Worn GENEActiv Accelerometer: A Cross-Sectional Study.

Introduction Objective methods like accelerometers are feasible for large studies and may quantify variability in day-to-day physical activity better than self-report. The variability between days suggests that day of the week cannot be ignored in the design and analysis of physical activity studies. The purpose of this paper is to investigate the optimal number of days needed to obtain reliable estimates of weekly habitual physical activity using the wrist-worn GENEActiv accelerometer. Methods Data are from a subsample of the Mitchelstown cohort; 475 (44.6% males; mean aged 59.6±5.5 years) middle-aged Irish adults. Participants wore the wrist GENEActiv accelerometer for 7-consecutive days. Data were collected at 100Hz and summarised into a signal magnitude vector using 60s epochs. Each time interval was categorised according to intensity based on validated cut-offs. Spearman pairwise correlations determined the association between days of the week. Repeated measures ANOVA examined differences in average minutes across days. Intraclass correlations examined the proportion of variability between days, and Spearman-Brown formula estimated intra-class reliability coefficient associated with combinations of 1–7 days. Results Three hundred and ninety-seven adults (59.7±5.5yrs) had valid accelerometer data. Overall, men were most sedentary on weekends while women spent more time in sedentary behaviour on Sunday through Tuesday. Post hoc analysis found sedentary behaviour and light activity levels on Sunday to differ to all other days in the week. Analysis revealed greater than 1 day monitoring is necessary to achieve acceptable reliability. Monitoring frame duration for reliable estimates varied across intensity categories, (sedentary (3 days), light (2 days), moderate (2 days) and vigorous activity (6 days) and MVPA (2 days)). Conclusion These findings provide knowledge into the behavioural variability in weekly activity patterns of middle-aged adults. Since Sunday differed from all other days in the week this suggests that day of the week cannot be overlooked in the design and analysis of physical activity studies and thus should be included in the study monitoring frames. Collectively our data suggest that six days monitoring, inclusive of Saturday and Sunday, are needed to reliably capture weekly habitual activity in all activity intensities using the wrist-worn GENEActiv accelerometer.