Towards volumetric thresholds in RECIST 1.1: Therapeutic response assessment in hepatic metastases.

OBJECTIVES: To empirically determine thresholds for volumetric assessment of response and progress of liver metastases in line with the unidimensional RECIST thresholds. METHODS: Patients with metastatic colorectal cancer initially enrolled in a multicentre clinical phase-III trial were included. In all CT scans, the longest axial diameters and volumes of hepatic lesions were determined semi-automatically. The sum of diameters and volumes of 1, ≤2 and ≤5 metastases were compared to all previous examinations. Volumetric thresholds corresponding to RECIST 1.1 thresholds were predicted with loess-regression. In sensitivity analysis, the concordances of proposed thresholds, weight-maximizing thresholds and thresholds from loess-regression were compared. Classification concordance for measurements of ≤2 metastases was further analyzed. RESULTS: For measurements of ≤2 metastases, 348 patients with 629 metastases were included, resulting in 4,773 value pairs. Regression analysis yielded volumetric thresholds of -65.3% for a diameter change of -30%, and +64.6% for a diameter change of +20%. When comparing measurements of unidimensional RECIST assessment with volumetric measurements, there was a concordance of significant progress (≥+20% and ≥+65%) in 88.3% and of significant response (≤-30% and ≤-65%) in 85.0%. CONCLUSIONS: In patients with hepatic metastases, volumetric thresholds of +65% and -65% were yielded corresponding to RECIST thresholds of +20% and -30%. KEY POINTS: • Volumes and diameters of liver metastases from colorectal cancer were determined. • Volumetric thresholds of +65%/-65% corresponding to RECIST 1.1 are proposed. • Comparing both measurements, concordance was 88.3% (significant progress) and 85.0% (significant response).

CT attenuation of liver metastases before targeted therapy is a prognostic factor of overall survival in colorectal cancer patients. Results from the randomised, open-label FIRE-3/AIO KRK0306 trial.

OBJECTIVES: To assess the prognostic value of pre-therapeutic computed tomography (CT) attenuation of liver metastases for overall survival (OS) in metastatic colorectal cancer (mCRC). METHODS: In the open-label, randomised, prospective phase-III FIRE-3 trial, patients with histologically confirmed mCRC received fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) with either cetuximab or bevacizumab. Participating patients gave written informed consent prior to study entry. In CT at baseline (portal venous phase, slice thickness ≤5 mm), mean attenuation [Hounsfield units (HU)] of liver metastases was retrospectively assessed by semi-automated volumetry. Its prognostic influence on OS was analysed in Kaplan-Meier-analysis and Cox proportional hazard regression and an optimal threshold was determined. RESULTS: In FIRE-3, 592 patients were enrolled between 2007 and 2012. Among the 347 patients eligible for liver volumetry, median baseline CT attenuation of liver metastases was 59.67 HU [interquartile range (IQR), 49.13, 68.85]. Increased attenuation was associated with longer OS {per 10 HU: hazard ratio (HR), 0.85 [95% confidence interval (CI), 0.78, 0.93], p < 0.001}. The optimised threshold (≥61.62 HU) was a strong predictor for increased OS [median, 21.3 vs 30.6 months; HR, 0.61 (95% CI, 0.47, 0.80), p < 0.001]. Multivariate regression controlling for correlated and further prognostic factors confirmed this [HR, 0.60 (95% CI, 0.45, 0.81), p = 0.001]. Furthermore, mean attenuation ≥61.62 HU was significantly associated with increased early tumour shrinkage (p = 0.002) and increased depth of response (p = 0.012). CONCLUSIONS: Increased mean baseline CT attenuation of liver metastases may identify mCRC patients with prolonged OS and better tumour response. KEY POINTS: • In colorectal cancer, increased attenuation of liver metastases in baseline computed tomography is a prognostic factor for prolonged OS (p < 0.001). • A threshold of ≥61.62 HU was determined as optimal cut-off to identify patients with prolonged OS (p < 0.001), early tumour shrinkage (p = 0.002) and increased depth of response (p = 0.012).

Early CT perfusion mismatch in acute stroke is not time-dependent but relies on collateralization grade.

INTRODUCTION: Factors that determine the extent of the penumbra in the initial diagnostic workup using whole brain CT Perfusion (WB-CTP) remain unclear. The purpose of the current study was to determine a possible dependency of the initial mismatch size between cerebral blood flow (CBF) and cerebral blood volume (CBV) from time after symptom onset, leptomeningeal collateralization, and occlusion localization in acute middle cerebral artery (MCA) infarctions. METHODS: Out of an existing cohort of 992 consecutive patients receiving multiparametric CT scans including WB-CTP due to suspected stroke, we included patients who had (1) a witnessed time of symptom onset, (2) an infarction of the MCA territory as documented by follow-up imaging, and (3) an initial CBF volume of >10 ml. CBF and CBV lesion sizes, collateralization grade, and the site of occlusion were determined. RESULTS: We included 103 patients. Univariate analysis showed that time from symptom onset (168 +/- 91.2 min) did not correlate with relative or absolute mismatch volumes (p = 0.458 and p = 0.921). Higher collateralization gradings were associated with small absolute mismatch volumes (p = 0.004 and p < 0.001). Internal carotid artery (ICA) occlusions were associated with large absolute mismatch volumes (p = 0.004). Multivariate analysis confirmed that ICA occlusion was associated with large absolute mismatch volumes (p = 0.005), and high collateral grade was associated with small absolute mismatch volumes (p = 0.017). CONCLUSIONS: There is no significant correlation between initial CTP mismatch and time after symptom onset. Predictors of mismatch size include the extent of the collaterals and a proximal location of the occlusion.

Vertebral artery hypoplasia: frequency and effect on cerebellar blood flow characteristics.

BACKGROUND AND PURPOSE: Vertebral artery hypoplasia (VAH) is supposed to be a risk factor for posterior circulation ischemia (PCI), particularly in the territory of the posterior inferior cerebellar artery (PICA). The aim of our study was to determine whether VAH impedes perfusion in the dependent PICA territory even in the absence of manifest PCI. METHODS: VA diameter was retrospectively measured in 934 consecutive patients who underwent whole-brain multimodal computed tomography because of suspected stroke. VAH was defined by a diameter of ≤2 mm and an asymmetry ratio of ≤1:1.7 of both VAs. We performed blinded computed tomography perfusion reading in patients with VAH without PCI (MRI-confirmed) and in control patients (ratio 1:2) with normal VAs. Four different perfusion maps were evaluated for a relative hypoperfusion in the PICA territory. RESULTS: VAH was found in 146 of 934 patients (15.6%). It was more frequent on the right side (66.1%). Of 146 patients, 59 without PCI qualified for computed tomography perfusion analysis. Depending on the perfusion map, ≤42.4% (25/59) of patients with VAH, but only 7.6% (9/118) without VAH, showed an ipsilateral PICA hypoperfusion (P<0.001). Sensitivities in patients with VAH were as follows: time to drain 42.4% (25/59)>mean transit time 39.0% (23/59)>cerebral blood flow 25.4% (15/59). Cerebral blood volume was never affected. CONCLUSIONS: VAH is a frequent vascular variant that can lead to a relative regional hypoperfusion in the PICA territory. Additional research should clarify the pathophysiological role of VAH in PCI.

Whole-brain CT perfusion: reliability and reproducibility of volumetric perfusion deficit assessment in patients with acute ischemic stroke.

INTRODUCTION: The aim of this study was to examine reliability and reproducibility of volumetric perfusion deficit assessment in patients with acute ischemic stroke who underwent recently introduced whole-brain CT perfusion (WB-CTP). METHODS: Twenty-five consecutive patients underwent 128-row WB-CTP with extended scan coverage of 100 mm in the z-axis using adaptive spiral scanning technique. Volumetric analysis of cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), time to peak (TTP), and time to drain (TTD) was performed twice by two blinded and experienced readers using OsiriX V.4.0 imaging software. Interreader agreement and intrareader agreement were assessed by intraclass correlation coefficients (ICCs) and Bland-Altman Analysis. RESULTS: Interreader agreement was highest for TTD (ICC 0.982), followed by MTT (0.976), CBF (0.955), CBV (0.933), and TTP (0.865). Intrareader agreement was also highest for TTD (ICC 0.993), followed by MTT (0.988), CBF (0.981), CBV (9.953), and TTP (0.927). The perfusion deficits showed the highest absolute volumes in the time-related parametric maps TTD (mean volume 121.4 ml), TTP (120.0 ml), and MTT (112.6 ml) and did not differ significantly within this group (each with p > 0.05). In comparison to time-related maps, the mean CBF perfusion deficit volume was significantly smaller (92.1 ml, each with p < 0.05). The mean CBV lesion size was 23.4 ml. CONCLUSIONS: Volumetric assessment in WB-CTP is reliable and reproducible. It might serve for a more accurate assessment of stroke outcome prognosis and definition of flow-volume mismatch. Time to drain showed the highest agreement and therefore might be an interesting parameter to define tissue at risk.

Semi-automatic CT-angiography based evaluation of the aortic annulus in patients prior to TAVR: interchangeability with manual measurements.

To compare a semi-automatic software tool for the measurement of aortic annulus dimensions with manual measurements by expert readers and to analyze whether and to what extent interchangeability exists between semi-automatic and manual measurements. We retrospectively included 374 consecutive patients with high-grade aortic stenosis who had undergone CT-angiography of the heart prior to trans-catheter aortic valve replacement (TAVR). In independent analyses, two expert readers manually measured aortic annulus dimensions (long axis, short axis, circumference, area) as well as the distance of the coronary ostia from the annulus plane. A third independent reader performed annulus evaluation using a software tool for semi-automatic detection and measurement of the annulus plane. Intraclass correlation coefficients (ICC) and Bland-Altman analysis was used to compare both manual measurements as well as manual and semi-automatic measurements of annulus parameters. Using the respective measurements we simulated size selection for a Sapien XT transcatheter heart valve (THV). Interchangeability of methods was addressed by calculation of the estimated individual equivalence index γ. There was excellent agreement between both expert observers in manual measurements of the annulus with ICC's in the range 0.89-0.94 for all anatomic parameters. Similar high agreements were observed between semi-automatic and manual measurements, with ICC's in the range of 0.89-0.95. THV size recommendation based on manual versus semiautomatic measurements agreed in 80.7% of cases while agreement between both expert readers concerning THV size recommendation was 80.6%. Semi-automatic measurements of anatomic parameters of the aortic root show high agreement and interchangeability with manual measurements in CT-angiography prior to TAVR.

Prognostic value of radiologically enlarged lymph nodes in patients with metastatic colorectal cancer: Subgroup findings of the randomized, open-label FIRE-3/AIO KRK0306 trial.

PURPOSE: To determine the prognostic impact of radiologically enlarged lymph nodes ≥ 10 mm on the survival of patients with metastatic colorectal cancer. MATERIALS AND METHODS: The prospective, randomized, open-label FIRE-3/AIO KRK0306 trial evaluated the first-line therapy of patients with KRAS exon 2 wild-type metastatic colorectal cancer with fluorouracil, folinic acid and irinotecan plus either cetuximab or bevacizumab. In the RAS wild-type population (n = 400), adequately evaluable baseline computed tomographies (n = 339) were reviewed for enlarged regional and distant lymph nodes. Their prognostic relevance was retrospectively analyzed in uni- and multivariable Cox proportional hazard regressions. RESULTS: Median overall survival was 21.7 months in patients with enlarged lymph nodes and 33.2 months in patients without (hazard rate ratio [HR] = 1.61, 95% confidence interval [CI], 1.23-2.09; P < 0.001). This was confirmed in multivariable analysis (HR = 1.37, 95% CI, 1.02-1.83; P = 0.036). Progression-free survival of patients with enlarged lymph nodes showed a consistent but insignificant trend (9.9 vs. 11.1 months; HR = 1.23, 95% CI, 0.98-1.54; P = 0.072). Enlarged lymph nodes were also associated with BRAF-mutations (P = 0.004). CONCLUSION: The presence of radiologically enlarged lymph nodes in baseline staging has a negative prognostic value beyond established and potential prognostic parameters.

Penumbra pattern assessment in acute stroke patients: comparison of quantitative and non-quantitative methods in whole brain CT perfusion.

BACKGROUND AND PURPOSE: While penumbra assessment has become an important part of the clinical decision making for acute stroke patients, there is a lack of studies measuring the reliability and reproducibility of defined assessment techniques in the clinical setting. Our aim was to determine reliability and reproducibility of different types of three-dimensional penumbra assessment methods in stroke patients who underwent whole brain CT perfusion imaging (WB-CTP). MATERIALS AND METHODS: We included 29 patients with a confirmed MCA infarction who underwent initial WB-CTP with a scan coverage of 100 mm in the z-axis. Two blinded and experienced readers assessed the flow-volume-mismatch twice and in two quantitative ways: Performing a volumetric mismatch analysis using OsiriX imaging software (MM(VOL)) and visual estimation of mismatch (MM(EST)). Complementarily, the semiquantitative Alberta Stroke Programme Early CT Score for CT perfusion was used to define mismatch (MM(ASPECTS)). A favorable penumbral pattern was defined by a mismatch of ≥ 30% in combination with a cerebral blood flow deficit of ≤ 90 ml and an MM(ASPECTS) score of ≥ 1, respectively. Inter- and intrareader agreement was determined by Kappa-values and ICCs. RESULTS: Overall, MM(VOL) showed considerably higher inter-/intrareader agreement (ICCs: 0.751/0.843) compared to MM(EST) (0.292/0.749). In the subgroup of large (≥ 50 mL) perfusion deficits, inter- and intrareader agreement of MM(VOL) was excellent (ICCs: 0.961/0.942), while MM(EST )interreader agreement was poor (0.415) and intrareader agreement was good (0.919). With respect to penumbra classification, MM(VOL) showed the highest agreement (interreader agreement: 25 agreements/4 non-agreements/κ: 0.595; intrareader agreement 27/2/0.833), followed by MM(EST) (22/7/0.471; 23/6/0.577), and MM(ASPECTS) (18/11/0.133; 21/8/0.340). CONCLUSION: The evaluated approach of volumetric mismatch assessment is superior to pure visual and ASPECTS penumbra pattern assessment in WB-CTP and helps to precisely judge the extent of 3-dimensional mismatch in acute stroke patients.