Discrepancies of assessments in a RECIST 1.1 phase II clinical trial - association between adjudication rate and variability in images and tumors selection.

BACKGROUND: In imaging-based clinical trials, it is common practice to perform double reads for each image, discrepant interpretations can result from these two different evaluations. In this study we analyzed discrepancies that occurred between local investigators (LI) and blinded independent central review (BICR) by comparing reader-selected imaging scans and lesions. Our goal was to identify the causes of discrepant declarations of progressive disease (PD) between LI and BICR in a clinical trial. METHODS: We retrospectively analyzed imaging data from a RECIST 1.1-based, multi-sites, phase II clinical trial of 179 patients with adult small cell lung cancer, treated with Cabazitaxel compared to Topotecan. Any discrepancies in the determination of PD between LI and BICR readers were reviewed by a third-party adjudicator. For each imaging time point and reader, we recorded the selected target lesions, non-target lesions, and new lesions. Odds ratios were calculated to measure the association between discrepant declarations of PD and the differences in reviewed imaging scans (e.g. same imaging modality but with different reconstruction parameters) and selected lesions. Reasons for discrepancies were analyzed. RESULTS: The average number of target lesions found by LI and BICR was respectively 2.9 and 3.4 per patient (p < 0.05), 18.4% of these target lesions were actually non-measurable. LI and BICR performed their evaluations based on different baseline imaging scans for 59% of the patients, they selected at least one different target lesion in 85% of patients. A total of 36.7% of patients required adjudication. Reasons of adjudication included differences in 1) reporting new lesions (53.7%), 2) the measured change of the tumor burden (18.5%), and 3) the progression of non-target lesions (11.2%). The rate of discrepancy was not associated with the selection of non-measurable target lesions or with the readers' assessment of different images. Paradoxically, more discrepancies occurred when LI and BICR selected exactly the same target lesions at baseline compared to when readers selected not exactly the same lesions. CONCLUSIONS: For a large proportion of evaluations, LI and BICR did not select the same imaging scans and target lesions but with a limited impact on the rate of discrepancy. The majority of discrepancies were explained by the difference in detecting new lesions. TRIAL REGISTRATION: ARD12166 ( https://clinicaltrials.gov/ct2/show/NCT01500720 ).

Predictive factors for treatment response using dual-energy computed tomography in patients with advanced lung adenocarcinoma.

PURPOSE: This study aimed to investigate whether the quantitative parameters of dual-energy computed tomography (DECT) can predict the effects of chemotherapy in advanced adenocarcinoma based on the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. MATERIALS AND METHODS: A total of 90 patients (59 males, 31 females, age 61.4 ±â€¯12.3 (23-85)) with unresectable lung adenocarcinoma (TNM stage IIIB or IV) who underwent DECT before chemotherapy were prospectively included in this study. By comparing baseline studies with the best response achieved during 1 st line chemotherapy, patients were divided into two groups according to RECIST (version 1.1) guidelines as follows; responders (CR or PR) and non-responders (SD or PD). Quantitative measurements were performed on baseline DECT, and a logistic regression model was used to evaluate predictive factors for a response to chemotherapy. RESULTS: Among 90 patients, 38 were categorized as responders, while 52 patients were non-responders. The mean iodine concentration measurements were significantly higher in responders compared with non-responders (1.81 ±â€¯0.51 vs 1.33 ±â€¯0.76 mg/ml, p < 0.001). On multivariate analysis, EGFR mutation (odds ratio (OR): 3.116, 95% confidential interval (CI):1.182-8.213, p = .019) and iodine concentration (OR: 1.112, 95% CI:1.034-1.196, p = .006) were found to be significant for predicting a treatment response. CONCLUSIONS: Dual-energy CT using a quantitative analytic method based on iodine concentration measurements can be used to predict the effects of chemotherapy in patients with advanced adenocarcinoma.

Three-Dimensional Ground Glass Opacity Ratio in CT Images Can Predict Tumor Invasiveness of Stage IA Lung Cancer.

PURPOSE: We investigated the relationship between various parameters, including volumetric parameters, and tumor invasiveness according to the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification. MATERIALS AND METHODS: We retrospectively reviewed 99 patients with completely resected stage IA lung adenocarcinoma. The correlation between several parameters [one-dimensional ground glass opacity (1D GGO) ratio, two-dimensional (2D) GGO ratio, three-dimensional (3D) GGO ratio, 1D solid size, 2D solid size, and 3D solid size] and tumor invasiveness according to IASLC/ATS/ERS classification was investigated using receiver operating characteristic (ROC) analysis. Adenocarcinoma in situ and minimally invasive adenocarcinoma were referred to as noninvasive adenocarcinoma. RESULTS: The areas under the curve (AUC) to predict invasive adenocarcinoma for the 1D, 2D, and 3D GGO ratios were 0.962, 0.967, and 0.971, respectively. The optimal cut-off values for the 1D, 2D, and 3D GGO ratios were 38%, 62%, and 74%, respectively. The AUC values for 1D, 2D, and 3D solid sizes to predict invasive adenocarcinoma were 0.933, 0.944, and 0.903, respectively. The optimal cut-off values for 1D, 2D, and 3D solid sizes were 1.2 cm, 1.5 cm², and 0.7 cm³, respectively. The difference in the ROC curves for 3D GGO ratio and 3D solid size was significant (p=0.01). CONCLUSION: Computed tomography image-related parameters based on GGO were well correlated with and predictive of invasiveness according to IASLC/ATS/ERS classification. 3D GGO ratio was more strongly correlated with pathologic invasiveness than 3D solid size.

Predictors of False-Negative Results from Percutaneous Transthoracic Fine-Needle Aspiration Biopsy: An Observational Study from a Retrospective Cohort.

PURPOSE: We investigated factors predictive of false-negative pulmonary lesions with nonspecific benign cytology results on percutaneous transthoracic fine-needle aspiration biopsy (FNAB). MATERIALS AND METHODS: We included 222 pulmonary lesions that had a nonspecific benign result from percutaneous transthoracic FNAB between March 2005 and December 2012, and were confirmed by subsequent pathologic results or adequate clinical follow up over at least 2 years. Clinical, imaging, and biopsy procedure-related findings were compared between lesions with a final diagnosis of malignancy (false-negative) and lesions with a benign diagnosis (true-negative). Multivariate logistic regression analysis was performed to identify significant predictors of false-negatives. RESULTS: Of 222 lesions, 115 lesions were proved to be false-negatives, and 107 were true-negatives. Compared with the true-negatives, false-negative lesions showed significantly older age (p=0.037), higher maximum standardized uptake value (SUVmax) on positron emission tomography (p=0.001), larger lesion size (p=0.007), and lesion characteristics of a subsolid nodule (p=0.007). On multivariate logistic regression analysis, SUVmax, lesion size, and lesion characteristics were significant predictors of false-negative results. CONCLUSION: Among the clinical, radiologic, and procedure-related factors analyzed, high SUVmax, large lesion size, and subsolid lesions were useful for predicting malignancy in pulmonary lesions with nonspecific benign cytology results on FNAB.

Correlation between EGFR gene mutation, cytologic tumor markers, 18F-FDG uptake in non-small cell lung cancer.

BACKGROUND: EGFR mutation-induced cell proliferation causes changes in tumor biology and tumor metabolism, which may reflect tumor marker concentration and 18F-FDG uptake on PET/CT. Direct aspirates of primary lung tumors contain different concentrations of tumor markers than serum tumor markers, and may correlate better with EGFR mutation than serum tumor markers. The purpose of this study is to investigate an association between cytologic tumor markers and FDG uptake with EGFR mutation status in non-small cell lung cancer (NSCLC). METHODS: We prospectively collected tumor aspirates of 61 patients who underwent EGFR mutation analysis. Serum and cytologic CYFRA 21-1, CEA, and SCCA levels were measured and correlated with EGFR gene mutations. FDG PET/CT was performed on 58 patients for NSCLC staging, and SUV was correlated with EGFR mutation status. RESULTS: Thirty (50%) patients had EGFR mutation and 57 patients had adenocarcinoma subtype. Univariate analysis showed that female gender, never smoker, high levels of cytologic CYFRA 21-1 (c-CYFRA) and lower maximum standard uptake value (SUVmax) were correlated with EGFR mutations. ROC generated cut-off values of 20.8 ng/ml for c-CYFRA and SUVmax of 9.6 showed highest sensitivity for EGFR mutation detection. Multivariate analysis revealed that female gender [hazard ratio (HR): 18.15, p = 0.025], higher levels of c-CYFRA (HR: 7.58, and lower SUVmax (HR: 0.08, p = 0.005) were predictive of harboring EGFR mutation. CONCLUSIONS: The cytologic tumor marker c-CYFRA was positively associated with EGFR mutations in NSCLC. EGFR mutation-positive NSCLCs have relatively lower glycolysis compared with NSCLCs without EGFR mutation.

Prognostic impact of cytological fluid tumor markers in non-small cell lung cancer.

The serum tumor markers CYFRA 21-1, carcinoembryonic antigen (CEA), and squamous cell carcinoma antigen (SCCA) are useful in diagnosis and prognosis of non-small cell lung cancer (NSCLC). Cytologic tumor markers obtained during needle aspiration biopsies (NAB) of lung lesions are useful for NSCLC diagnosis. This study investigated the incremental prognostic value of cytologic tumor markers compared to serum tumor markers. This prospective study included 253 patients diagnosed with NSCLC by NAB with cytologic tumor marker analysis. Levels of cytologic CYFRA 21-1, CEA, SCCA, and their serum counterparts were followed up for survival analysis. Optimal cutoff values for each tumor marker were obtained for overall survival (OS) and progression-free survival (PFS) analyses. All patients were followed up for a median of 22.8 months. Using cutoff values of 0.44 ng/ml for C-SCCA, 2.0 ng/ml for S-SCCA, and 3.3 ng/ml for S-CYFRA, a multivariate analysis revealed that high S-SCCA (hazard ratio, HR, 1.84) and high C-SCCA (HR, 1.63) were independent predictive factors of OS. The 3-year overall survival rate was 55 vs. 80 % for high and low C-SCCA, respectively. Cytologic tumor marker level detection is easily obtainable and provides prognostic information for NSCLC. Cytologic tumor markers provide comparable prognostic information relative to serum tumor markers, with C-SCCA acting as a strong prognostic factor of overall survival and PFS.

Accuracy of CT for Selecting Candidates for Coronary Artery Bypass Graft Surgery: Combination with the SYNTAX Score.

PURPOSE: To investigate the diagnostic performance of coronary computed tomographic (CT) angiography for selecting candidates for coronary artery bypass graft (CABG) surgery according to the 2011 American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) guidelines for CABG surgery and determine the added value of SYNTAX (Synergy between PCI with TAXUS and Cardiac Surgery) scoring for selecting CABG surgery candidates. MATERIALS AND METHODS: Approval was obtained from the Institutional Review Board, and informed consent was waived for this retrospective study. A total of 399 patients (mean age, 63.8 years; 244 men and 155 women) who underwent both coronary CT angiography and invasive coronary angiography were included. Eligible criteria for CABG surgery were established on the basis of the 2011 ACCF/AHA guidelines. RESULTS: from coronary CT angiography and invasive coronary angiography were retrospectively reviewed, and SYNTAX scores were determined. The diagnostic performance of coronary CT angiography for selecting CABG surgery candidates was calculated with invasive coronary angiography as the reference method. The diagnostic performance of coronary CT angiography alone, the CT-based SYNTAX score, and the combined coronary CT angiography with CT-based SYNTAX score were assessed by using a combination of invasive coronary angiography and invasive coronary angiography-based SYNTAX scores as a reference method. Statistical analyses were performed by using the generalized estimating equation, independent t test, Mann-Whitney U test, Wilcoxon signed rank test, Fisher exact test, and χ(2) statistics. RESULTS: The overall sensitivity, specificity, positive predictive value (PPV), and negative predictive value of coronary CT angiography for selecting CABG surgery candidates were 96.5%, 96.5%, 88.3%, and 99.0%, respectively. When a combination of invasive coronary angiography with an invasive coronary angiography-based SYNTAX score was used as a standard reference, combined coronary CT angiography with a CT-based SYNTAX score had higher specificity and PPV (98.3% and 86.0%, respectively) than did coronary CT angiography alone (84.5% and 40.4%, respectively; P < .0001). CONCLUSION: Coronary CT angiography had diagnostic accuracy comparable to that of invasive coronary angiography for selecting CABG surgery candidates, and combining a CT-based SYNTAX score with coronary CT angiography can be a highly specific method for selecting CABG surgery candidates.

Predictors of Recurrent Stroke in Patients with Ischemic Stroke: Comparison Study between Transesophageal Echocardiography and Cardiac CT.

PURPOSE: To investigate cardiac computed tomographic (CT) findings predictive of recurrent stroke in patients with ischemic stroke and determine the incremental risk stratification benefit of cardiac CT findings compared with transesophageal echocardiography (TEE) findings in patients with ischemic stroke. MATERIALS AND METHODS: This single-center prospective study protocol was approved by the institutional review boards, and written informed consent was obtained from all patients. Among 548 consecutive patients, 374 patients with ischemic stroke (254 men and 120 women, with a mean age of 63.1 years) who underwent TEE and cardiac CT were prospectively enrolled in this study. TEE and cardiac CT images were assessed for cardioembolic sources, including thrombus, tumor, spontaneous echo contrast, valvular vegetation, atrial septal aneurysm, patent foramen ovale, and aortic plaque. The primary end point was stroke recurrence. Prognostic factors were assessed with Cox univariate and multivariate analysis. The integrated area under the receiver operating characteristic curve was calculated to compare the prognostic abilities of CT and TEE parameters. RESULTS: During a median follow-up period of 433 days, there were a total of 28 recurrent stroke events. The TEE parameter of plaque complexity (hazard ratio, 13.512; 95% confidence interval: 3.668, 49.778; P < .001) and CT parameter of plaque complexity (hazard ratio, 32.538; 95% confidence interval: 7.544, 140.347; P < .001) were predictors of recurrent stroke. The time-dependent receiver operating characteristic curve analysis demonstrated no significant differences in prediction of recurrent stroke between TEE and CT parameters (integrated area under the receiver operating characteristic curve, 0.812 vs 0.840, respectively). CONCLUSION: Complex aortic plaque evaluated with cardiac CT and TEE was associated with an increased risk of stroke recurrence in patients with ischemic stroke.

Usefulness of thin-section single-shot turbo spin echo with half-Fourier acquisition in evaluation of local invasion of lung cancer.

PURPOSE: To evaluate the usefulness of thin-section single-shot turbo spin echo with half-Fourier acquisition (SS-TSE-HF) alone for evaluation of local invasion of lung cancer. MATERIALS AND METHODS: Our Institutional Review Board approved this retrospective study. Thirty-six patients with lung cancer who underwent magnetic resonance imaging (MRI) for evaluation of local invasion followed by curative surgery from July 2008 to June 2012 were enrolled in this study. Two reviewers independently and blindly reviewed computed tomography (CT) and MRI (thin-section SS-TSE-HF and conventional MRI, which consisted of conventional axial SS-TSE-HF, dynamic MRI with respiratory and/or cardiac cine, and T1 -weighted high-resolution isotropic volume examination [THRIVE]) for the presence of local invasion. Diagnostic performances were evaluated using gross surgical findings and pathological results as a standard reference. RESULTS: The overall diagnostic performance for detecting local invasion of lung cancer between the two reviewers were as follows: specificity and accuracy of thin-section SS-TSE-HF (89.0% and 87.5%) were significantly higher than those of CT (25.6% and 46.9%, P < 0.001 for both) or conventional MRI (61.0% and 69.5%, P < 0.001 and P = 0.008, respectively). Sensitivity was 84.8% for thin-section SS-TSE-HF with the same value for CT (P = 0.246) and conventional MRI (P = 0.209). CONCLUSION: Thin-section SS-TSE-HF sequence alone without any contrast agent demonstrated a relatively high diagnostic performance in evaluation of local invasion of lung cancer.

Dual-energy cardiac computed tomography for differentiating cardiac myxoma from thrombus.

Although intra-cardiac masses are rare, diagnosis and refined characterization of these masses are important because of the different therapeutic strategies used to treat these lesions. The purpose of this study was to evaluate the diagnostic value of dual-energy cardiac computed tomography (CCT) for differentiating cardiac myxomas from thrombi. Our institutional review board approved this study, and patients provided informed consent. We prospectively enrolled 37 patients who had an intra-cardiac mass on echocardiography or computed tomography (CT). All patients underwent dual-energy CCT. For quantitative analysis, the CT attenuation density and iodine concentration of the intra-cardiac mass were measured on CT images. The Mann-Whitney test was used to evaluate differences in the mean CT attenuation density and the mean iodine concentrations between the cardiac myxoma and thrombus groups. Pathological results or follow-up with echocardiography was used to make the final diagnosis. There were a total of 17 cardiac myxomas and 20 thrombi. On CT, the mean CT numbers were not significantly different between cardiac myxomas and cardiac thrombi (91.7 ± 11.6 HU vs. 85.2 ± 10.9 HU, respectively, P = 0.241), whereas, the mean iodine concentration (mg/ml) was significantly different between cardiac myxomas and cardiac thrombi (3.53 ± 0.72 vs. 1.37 ± 0.31, respectively, P < 0.001). Dual-energy CCT using a quantitative analytic methodology can be used to differentiate between cardiac myxomas and thrombi.

Differentiation between mucus secretion and endoluminal tumors in the airway: analysis and comparison of CT findings.

OBJECTIVE: The objective of our study was to suggest CT features that help differentiate transient mucus secretion from airway tumors in the evaluation of soft-tissue nodular lesions confined within the airway lumen. MATERIALS AND METHODS: Forty-two patients with airway tumors (mean age, 57.6 ± 14.9 [SD] years) and 48 patients with secretion (mean age, 67.8 ± 13.4 years) were included. Two observers analyzed the following features on contrast-enhanced CT in consensus readings: shape (round, ovoid, lobulating, or complex); margin (circumscribed or uncircumscribed); size (including change in size between mediastinal and lung window images); location (anterior, posterior, or unclear); angle between the lesion and contacting airway wall (acute, obtuse, or unclear); attenuation (quantitative and qualitative analyses); and presence of air, fat, or calcification within the lesion. The positive predictive value (PPV) of each CT finding was calculated for secretion and tumor, respectively. RESULTS: Round (90.0%) or lobulating (92.9%) shape, uncircumscribed margin (100.0%), unclear location (87.5%), unclear angle (87.5%), a CT number of 21.7 HU or more (91.7%), and internal features such as fat (100.0%) or calcification (100.0%) showed high PPVs for tumors. Complex shape (100.0%), change in size of more than 15.9% (96.8%), a CT number of less than 21.7 HU (83.3%), and internal air density (100.0%) showed high PPVs for secretion. CONCLUSION: On contrast-enhanced CT, the evaluation of shape, change in size between mediastinal and lung window images, the measurement of CT number, and internal features such as air, fat, or calcification might help differentiate secretion from tumors.

Respiratory dynamic magnetic resonance imaging for determining aortic invasion of thoracic neoplasms.

OBJECTIVE: An accurate radiological method for evaluating the presence or extent of aortic invasion by thoracic cancer is essential in the preoperative setting. The aim of this study was to assess whether respiratory dynamic (RD) magnetic resonance imaging (MRI) more accurately detects aortic invasion of mediastinal tumors and lung cancer compared with conventional MRI or computed tomography (CT). METHODS: Twenty-six patients (19 male, 7 female; mean age, 63.08 ± 12.05 years) with inconclusive evidence of aortic invasion on chest CT underwent MRI (conventional and RD MRI using a balanced fast field echo sequence with a 1.5 T unit). The presence of aortic invasion was determined by fixation of the aorta and lack of synchronous motion during respiration on RD MRI. The results of CT and MRI were compared with the pathology results. The sensitivity, specificity, and accuracy of CT, conventional MRI, and conventional MRI with RD MRI were compared. RESULTS: Of 26 patients, 5 patients had invasion of the aorta. The sensitivity for determining aortic invasion was 100% using CT alone, conventional MRI alone, and conventional MRI with RD MRI. The specificity and accuracy for conventional MRI with RD MRI were significantly higher (71.4% and 76.9%, respectively) than for CT (28.5% and 42.3%, P < .05) or conventional MRI alone (33.3% and 46.1%, P < .05). CONCLUSIONS: RD MRI may improve the diagnostic accuracy of MRI by predicting aortic invasion use in preoperative staging.