Accuracy of dual-source CT coronary angiography : first experience in a high pre-test probability population without heart rate control The aim of this study was to assess the diagnostic accuracy of dual-source computed tomography -LRB- DSCT -RRB- for evaluation of coronary artery disease -LRB- CAD -RRB- in a population with extensive coronary calcifications without heart rate control . Thirty patients -LRB- 24 male , 6 female , mean age 63.1 ± 11.3 years -RRB- with a high pre-test probability of CAD underwent DSCT coronary angiography and invasive coronary angiography -LRB- ICA -RRB- within 14 ± 9 days . No beta-blockers were administered prior to the scan . Two readers independently assessed image quality of all coronary segments with a diameter ≥ 1.5 mm using a four-point score -LRB- 1 : excellent to 4 : not assessable -RRB- and qualitatively assessed significant stenoses as narrowing of the luminal diameter > 50 % . Causes of false-positive -LRB- FP -RRB- and false-negative -LRB- FN -RRB- ratings were assigned to calcifications or motion artifacts . ICA was considered the standard of reference . Mean body mass index was 28.3 ± 3.9 kg/m2 -LRB- range 22.4 -- 36.3 kg/m2 -RRB- , mean heart rate during CT was 70.3 ± 14.2 bpm -LRB- range 47 -- 102 bpm -RRB- , and mean Agatston score was 821 ± 904 -LRB- range 0 -- 3,110 -RRB- . Image quality was diagnostic -LRB- scores 1 -- 3 -RRB- in 98.6 % -LRB- 414/420 -RRB- of segments -LRB- mean image quality score 1.68 ± 0.75 -RRB- ; six segments in three patients were considered not assessable -LRB- 1.4 % -RRB- . DSCT correctly identified 54 of 56 significant coronary stenoses . Severe calcifications accounted for false ratings in nine segments -LRB- eight FP/one FN -RRB- and motion artifacts in two segments -LRB- one FP/one FN -RRB- . Overall sensitivity , specificity , positive and negative predictive value for evaluating CAD were 96.4 , 97.5 , 85.7 , and 99.4 % , respectively . First experience indicates that DSCT coronary angiography provides high diagnostic accuracy for assessment of CAD in a high pre-test probability population with extensive coronary calcifications and without heart rate control . Introduction Recent advances in multi-detector-row computed tomography -LRB- CT -RRB- technology have continuously improved the quality of non-invasive coronary artery imaging . As a result , various studies have demonstrated a high accuracy of coronary angiography with 64-slice CT for the diagnosis of coronary artery disease -LRB- CAD -RRB- -LSB- 1 -- 8 -RSB- . In particular , the high negative predictive value has made non-invasive coronary angiography using 64-slice CT a modality that allows significant coronary stenoses to be reliably excluded . Consequently , the Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology has recently recommended in their guidelines that CT coronary angiography be performed in patients with stable angina who have a low pre-test probability of CAD , and an inconclusive exercise electrocardiogram -LRB- ECG -RRB- or stress imaging test -LSB- 9 -RSB- . To date , many studies have been published assessing the diagnostic performance of CT coronary angiography with different generations of scanners . Four-slice CT coronary angiography showed limited resolution and required long breath-hold times of nearly 40 s , resulting in a high number of vessel segments that could not be assessed -LSB- 10 -RSB- . Sixteen-slice CT coronary angiography showed improved diagnostic accuracy because of reduced breath-hold times and an increased temporal and spatial resolution -LSB- 11 , 12 -RSB- . Sixty-four-slice CT scanners were the first to allow highly accurate identification of significant coronary artery stenoses -LSB- 1 -- 8 -RSB- . However , data analysis in several of these studies could not be performed in all coronary artery segments , with a percentage of non-assessable segments of up to 12 % -LSB- 2 -RSB- . The main reasons were severe coronary artery wall calcifications and motion artifacts , the latter occurring especially with higher heart rates . Calcifications are known to complicate the assessment of coronary arteries -LSB- 10 -RSB- , however , some authors have suggested that substantial coronary calcification should not be used as a reason to defer CT coronary angiography -LSB- 13 -RSB- . In order to reduce motion artifacts , the administration of either intravenous or oral beta-blocker medication for heart rate control has been proposed even for 64-slice CT systems -LSB- 2 -- 6 , 8 , 11 , 14 -RSB- . In most studies , target heart rates for scanning were below 60 -- 65 beats per minute -LRB- bpm -RRB- . Another concept to comply with higher coronary velocities at higher heart rates is the use of multi-segment reconstruction algorithms that combine data from two or more consecutive cardiac cycles to improve temporal resolution at certain heart rates -LSB- 15 -RSB- . However , the latter approach relies on a complete periodicity of heart motion , limiting its use in patients with variable heart rates ; does not take into account the inter-heartbeat variability of coronary artery position ; and requires low pitch factors , prolonging data acquisition times -LSB- 16 -RSB- . In line with this , a recent 64-slice CT study demonstrated no significant overall benefit of multi-segment reconstruction with regard to image quality of coronary arteries -LSB- 17 -RSB- . The recently introduced dual-source CT -LRB- DSCT -RRB- scanner is characterized by two x-ray tubes and two corresponding detectors mounted onto the rotating gantry with an angular offset of 90 ° -LSB- 18 -RSB- . Regarding cardiac imaging capabilities , the new scanner system offers a high temporal resolution of 83 ms in a mono-segment reconstruction mode . Temporal resolution is independent of the heart rate , which is a major difference from single-source CT systems that rely on multi-segment reconstruction techniques . The first feasibility studies have shown promising results with DSCT coronary angiography regarding image quality of coronary arteries , cardiac valves , and left ventricular myocardium independent of the actual heart rate of the patient -LSB- 19 , 20 -RSB- . However , to date no study has investigated the diagnostic accuracy of DSCT coronary angiography for the diagnosis of CAD . The purpose of our study was to determine the performance of DSCT coronary angiography in diagnosing significant stenoses in comparison to invasive coronary angiography -LRB- ICA -RRB- in a high pre-test probability patient population without heart rate control . Materials and methods Patients In 30 patients -LRB- 6 women , 24 men ; mean age 63.1 ± 11.3 years ; age range 35 -- 86 years -RRB- who had undergone ICA for evaluation of suspected CAD , CT coronary angiography was performed within 30 days of catheterization -LRB- mean 14 ± 9 days -RRB- . Exclusion criteria for DSCT were allergy to iodine-containing contrast medium , renal insufficiency -LRB- creatinine level > 120 μmol/L -RRB- , pregnancy , hemodynamic instability , and previous stent graft placement or bypass surgery . Symptoms and cardiovascular risk factors of all patients are reported in Table 1 . Based on a previously published clinical pre-test score -LSB- 21 -RSB- , each patient in this population had a high pre-test probability of CAD . Patients with elevated or irregular heart rates were not excluded from the study . The study protocol was approved by our local ethics committee and all participating patients gave written informed consent . Table 1Synopsis of cardiovascular risk factors and symptomsFrequency -LRB- % -RRB- Risk factorsFamily history16 -LRB- 53 % -RRB- Obesity23 -LRB- 77 % -RRB- Dyslipidemia18 -LRB- 60 % -RRB- Diabetes19 -LRB- 63 % -RRB- Smoking25 -LRB- 83 % -RRB- Hypertension23 -LRB- 77 % -RRB- SymptomsAngina pectoris21 -LRB- 70 % -RRB- Probable angina pectoris7 -LRB- 23 % -RRB- Atypical chest pain2 -LRB- 7 % -RRB- Dual-source CT scan protocol All CT examinations were performed on a DSCT scanner -LRB- Somatom Definition , Siemens Medical Solutions , Forchheim , Germany -RRB- . The patients were centrally placed in the scanner to ensure that the entire heart was covered with the smaller field-of-view of the second tube detector array . Irrespective of the individual heart rate and the heart rate variability , no beta-blockers were given prior to the scan . Three patients took oral beta-blockers as part of their baseline medication . Nonenhanced DSCT for calcium scoring was performed from 1 cm below the level of the tracheal bifurcation to the diaphragm in a cranio-caudal direction using the following scanning parameters : detector collimation 32 × 0.6 mm , slice acquisition 64 × 0.6 mm by means of a z-flying focal spot , gantry rotation time 330 ms , pitch of 0.2 -- 0.39 adapted to the heart rate , tube current 80 mAs per rotation , and tube potential 120 kV . Thereafter , all patients received a single dose of 2.5 mg isosorbiddinitrate s. l. -LRB- Isoket , Schwarz Pharma , Monheim , Germany -RRB- -LSB- 22 -RSB- . After 2 min , the coronary angiography scan was started by continuously injecting a bolus of 80 ml of iodixanol -LRB- Visipaque 320 , 320 mg/mL , GE Healthcare , Buckinghamshire , UK -RRB- followed by 30 ml saline solution into an antecubital vein via an 18-gauge catheter -LRB- injection rate 5 mL/s -RRB- . Contrast agent application was controlled by bolus tracking . A region of interest -LRB- ROI ; mean diameter 10.1 ± 5.6 mm , range 7.5 -- 17.0 mm -RRB- was placed into the aortic root , and image acquisition started 5 s after the signal attenuation reached the predefined threshold of 100 Hounsfield units -LRB- HU -RRB- . Data acquisition was performed from 1 cm below the level of the tracheal bifurcation to the diaphragm in a cranio-caudal direction with a detector collimation of 32 × 0.6 mm , slice acquisition 64 × 0.6 mm by means of a z-flying focal spot , gantry rotation time 330 ms , pitch of 0.2 -- 0.43 adapted to the heart rate , tube current 400 mAs per rotation , and tube potential 120 kV . ECG-pulsing for radiation dose reduction was applied in all patients . At mean heart rates below 60 bpm , full tube current was applied from 60 to 70 % , at 61 -- 70 bpm from 50 to 80 % , and at heart rates above 70 from 30 to 80 % of the RR-interval . The electrocardiogram -LRB- ECG -RRB- was digitally recorded during data acquisition and was stored with the unprocessed CT dataset . Dual-source CT image reconstruction A retrospective gating technique was used to synchronize the data reconstruction with the ECG signal . A mono-segment reconstruction algorithm that uses the data from a quarter rotation of both detectors was used for image reconstruction -LSB- 18 -RSB- . In each patient , images were first reconstructed at 60 and 70 % of the RR-interval . If considered necessary , additional images were reconstructed in 5 % steps of the RR interval within the full tube current window . In case of irregular heart rates , the temporal variability in the reconstruction phase was compensated by manual ECG editing . In case of premature heart beats , the temporal window past the premature heart beat was deleted , and the next diastolic window was filled with one to three temporal windows to avoid data gaps . All ECG editing was performed by one experienced cardiovascular radiologist not involved in data read-out . For calcium scoring , non-overlapping images with a slice width of 3 mm were reconstructed using a medium-sharp convolution kernel -LRB- B35f -RRB- . For DSCT coronary angiography , images were reconstructed from the contrast-enhanced DSCT scan with a slice thickness of 0.75 mm , a reconstruction increment of 0.5 mm , and using a medium soft-tissue convolution kernel -LRB- B26f -RRB- . Depending on the individual anatomy , the reconstructed field-of-view -LRB- FoV -RRB- was adjusted to encompass the heart exactly -LRB- mean FoV 167 ± 19 mm ; range 131 -- 187 mm ; image matrix 512 × 512 pixels -RRB- . After removing patient and ECG information , all reconstructed images were transferred to a dedicated workstation -LRB- Wizard , Siemens Medical Solutions -RRB- equipped with dedicated cardiac post-processing software -LRB- Syngo Circulation , Siemens Medical Solutions -RRB- . Dual-source CT data analysis The mean Agatston score was calculated for each patient from the non-enhanced DSCT data with a detection threshold of 130 HU by using semi-automated software -LRB- Syngo Calcium Scoring , Siemens Medical Solutions -RRB- . For analysis of DSCT coronary angiography data , coronary arteries were segmented according to the guidelines of the American Heart Association -LSB- 23 -RSB- . The right coronary artery -LRB- RCA -RRB- was defined to include segments 1 -- 4 , the left main and left anterior descending artery -LRB- LM-LAD -RRB- to include segments 5 -- 10 , and the left circumflex artery -LRB- LCX -RRB- to include segments 11 -- 15 . The intermedial artery was designated as segment 16 , if present . All segments with a diameter of at least 1.5 mm at their origin were included . Diameter measurements were performed with an electronic caliper tool . Segments distal to an occluded vessel were excluded from analysis . All reconstructed images were evaluated and classified by two independent readers using axial source images , multi-planar reformations -LRB- MPR -RRB- , and thin-slab maximum intensity projections -LRB- MIP -RRB- on a per-segment basis . Both readers semi-quantitatively assessed the image quality of each coronary segment on a four-point ranking scale as previously published -LSB- 1 -RSB- : 1 , excellent -LRB- no artifacts , unrestricted evaluation -RRB- ; 2 , good -LRB- minor artifacts , good diagnostic quality -RRB- ; 3 , adequate -LRB- moderate artifacts , still acceptable and diagnostic -RRB- , and 4 , not assessable -LRB- severe artifacts impairing accurate evaluation -RRB- . Causes of image degradation were noted by both observers as arterial wall calcifications , motion artifacts , or others . Motion artifacts were defined as any impairment of image quality caused by vessel movement resulting in blurred or doubled vessel contours . Other reasons included low vessel opacification , low signal-to-noise ratio , and disturbing adjacent structures such as contrast-enhanced cardiac veins . In addition , both readers assessed all coronary artery segments for the presence of hemodynamically significant stenoses . Significant stenosis was defined as narrowing of the coronary luminal diameter exceeding 50 % . The vessel diameters were measured on reconstructions perpendicularly oriented to the vessel course . For any disagreement in data analysis , consensus agreement was achieved . Invasive coronary angiography ICA was performed according to standard techniques , and multiple views were stored on a CD-ROM . The angiograms were evaluated by one experienced observer who was blinded to the results of the DSCT coronary angiography . Coronary artery segments were defined according to the same guidelines mentioned above -LSB- 23 -RSB- . Each vessel segment was scored as being significantly stenosed , defined as a diameter reduction of > 50 % or not . Coronary artery analysis was performed in all vessels with a luminal diameter of at least 1.5 mm , excluding those vessels distal to complete occlusions . Statistical analysis Statistical analysis was performed using commercially available software -LRB- SPSS 12.0 , SPSS , Chicago , IL , USA -RRB- . Quantitative variables were expressed as mean ± SD and categorical variables as frequencies or percentages . In a subanalysis , patients were subdivided into mean heart rates of < 70 bpm and ≥ 70 bpm and into Agatston scores of < 400 and ≥ 400 . We took into account the clustered nature of the data -LRB- i.e. , the fact that there were not 420 independent vessel segments but instead clusters of segments in 30 patients -RRB- . Inter-observer agreements for image quality read-out and assessment of significant coronary artery stenoses were interpreted according to the guidelines of Landis and Koch -LSB- 24 -RSB- using the clustered data . Sensitivity , specificity , positive predictive value , and negative predictive value were calculated from chi-squared tests of contingency , and the 95 % confidence intervals -LRB- CI -RRB- were calculated from binomial expression on a per-segment basis . Because of the interdependencies between different segments , the statistics were also calculated on a per-patient basis -LRB- presence of at least one significant coronary artery stenosis or absence of any significant stenosis in each patient -RRB- . ICA was considered the standard of reference . Results DSCT and ICA were successfully performed in all patients without complications . The DSCT protocol was well tolerated by all patients , and all were able to hold their breath during data acquisition . The average HR during scanning was 70.3 ± 14.2 bpm -LRB- range 47 -- 102 bpm -RRB- . Seventeen patients -LRB- 56.7 % -RRB- had a heart rate below 70 bpm -LRB- mean 59.7 ± 5.9 bpm , range 47 -- 66 bpm -RRB- , while 13 patients -LRB- 43.3 % -RRB- had a heart rate of ≥ 70 bpm -LRB- mean 84.2 ± 8.4 bpm , range 72 -- 102 bpm -RRB- . Prevalance of coronary artery stenosis and calcium score A total of 56 coronary artery stenoses with a luminal narrowing of more than 50 % in diameter were identified in 15 patients -LRB- 50.0 % -RRB- using ICA . Single-vessel disease was present in 13.3 % -LRB- 4/30 -RRB- , two-vessel disease in 10.0 % -LRB- 3/30 -RRB- , and three-vessel disease in 26.7 % -LRB- 8/30 -RRB- . Significant coronary artery stenoses could be excluded in 15 patients -LRB- 50.0 % -RRB- . Calcified vessel wall deposits were present in 24 patients -LRB- 80 % -RRB- . Fourteen of these patients -LRB- 58.3 % -RRB- had significant coronary artery stenoses , while 10 patients -LRB- 41.7 % -RRB- had calcifications without significant stenoses . The mean Agatston score was 821 ± 904 -LRB- range 0 -- 3,110 -RRB- . Agatston score was < 400 in 15 patients -LRB- 50 % , mean score 85 ± 118 -RRB- and ≥ 400 in the other 15 patients -LRB- 50 % , mean score 1,483 ± 893 -RRB- . Image quality and image reconstruction intervals with DSCT A total of 420 coronary artery segments with a diameter ≥ 1.5 mm were evaluated -LRB- 11 segments were missing because of anatomical variants , 26 segments had a diameter less than 1.5 mm at their origin , and 9 segments were distal to an occluding stenosis -RRB- . An intermedial artery was present in 16 patients -LRB- 53.3 % -RRB- . Inter-observer agreement for image quality rating using clustered data was moderate -LRB- kappa = 0.68 -RRB- . The initially used reconstruction time-points of 60 and 70 % provided excellent image quality -LRB- score 1 -RRB- in 21.9 % -LRB- 92/420 -RRB- and 60.2 % -LRB- 253/420 -RRB- , respectively , while additional reconstructions were necessary in 17.9 % -LRB- 75/420 -RRB- to improve image quality . Whereas in the subgroup of patients with heart rates ≥ 70 bpm additional reconstructions at 30 to 50 % were considered necessary in 27.4 % -LRB- 48/175 -RRB- , in patients with heart rates < 70 bpm , the 60 and 70 % interval provided excellent image quality -LRB- score 1 -RRB- in 90.2 % of the segments -LSB- 30.2 % -LRB- 74/245 -RRB- and 60.0 % -LRB- 147/245 -RRB- , respectively -RSB- . Using the individual reconstruction interval with best image quality for each segment , image quality was excellent -LRB- score 1 -RRB- in 47.4 % of the coronary segments -LRB- 199/420 -RRB- , good -LRB- score 2 -RRB- in 37.9 % -LRB- 159/420 -RRB- , adequate -LRB- score 3 -RRB- in 13.3 % -LRB- 56/420 -RRB- , and poor/not assessable in 1.4 % -LRB- 6/420 -RRB- . Non-assessable -LRB- score 4 -RRB- coronary artery segments -LRB- segment 4 , n = 2 ; segment 8 , n = 1 ; segment 10 , n = 2 ; and segment 14 , n = 1 -RRB- were present in three patients with heart rates of 72 , 77 , and 86 bpm , and Agatston scores of 30 , 616 , and 0 , respectively . In the 221 segments with image quality rated other than excellent -LRB- score 1 -RRB- , reasons for impaired image quality were arterial wall calcifications in 48.9 % -LRB- 108/221 -RRB- , motion artifacts in 46.6 % -LRB- 103/221 -RRB- , or other in 4.5 % of segments -LRB- 10/221 ; low signal-to-noise ratio , n = 5 ; low vessel opacification , n = 4 ; overlaying adjacent structures , n = 1 -RRB- . At heart rates ≥ 70 bpm , minor to moderate motion artifacts accounted for 68.2 % -LRB- 73/107 -RRB- of image quality impairment , while in patients with an Agatston score ≥ 400 , severe arterial wall calcifications were mainly responsible for decreased image quality -LSB- 76.4 % -LRB- 94/123 -RRB- -RSB- . Diagnostic accuracy of DSCT in comparison to ICA The kappa value for coronary artery stenosis detection with DSCT was 0.83 indicating a good inter-observer agreement . DSCT coronary angiography correctly recognized 54 of the 56 significant stenoses -LRB- 96.4 % -RRB- detected with ICA . For both readers , nine false-positive -LRB- FP -RRB- and two false-negative -LRB- FN -RRB- ratings occurred with DSCT coronary angiography . Causes of FP and FN ratings were massive calcifications in nine segments -LRB- eight FP , one FN -RRB- and motion artifacts in two segments -LRB- one FP , one FN -RRB- . The two FN ratings occurred in segments 8 and 9 . Examples of three patients with suspicion of CAD who underwent DSCT coronary angiography are provided in Figs. 1 , 2 , and 3 . Fig. 1a , bDual-source CT coronary angiography in a 62-year-old woman with suspected coronary artery disease -LRB- mean heart rate during scanning 76 bpm , Agatston score 0 -RRB- . a Curved thin-slab maximum-intensity projections through the centerline of the right coronary -LRB- RCA -RRB- , left anterior descending -LRB- LAD -RRB- , and left circumflex artery -LRB- LCX -RRB- . Slight blurring of the mid-RCA and mid-LAD rendered image quality as good -LRB- score 2 -RRB- in these segments , while image quality was rated excellent -LRB- score 1 -RRB- in all other segments . Coronary artery disease could be reliably excluded in this patient . b Volume-rendered image of the left coronary arteries and of the proximal RCA -LRB- insert -RRB- demonstrates accurate depiction of the coronary artery treeFig . 2a , bDual-source CT coronary angiography in a 69-year-old man with suspected coronary artery disease -LRB- mean heart rate during scanning 77 bpm , Agatston score 1,316 -RRB- . a Curved-planar reconstruction of the right coronary artery demonstrates high-grade coronary artery stenosis of the proximal segment -LRB- arrow -RRB- and non-significant stenoses of the mid and distal segments -LRB- arrowheads -RRB- . b Invasive coronary angiography in a left anterior oblique projection -LRB- 45 ° -RRB- confirms significant stenosis of the proximal segment of the right coronary artery -LRB- arrow -RRB- and non-significant stenoses of the mid and distal segments -LRB- arrowheads -RRB- Fig. 3a , bDual-source CT scan in a 73-year-old man with suspected coronary artery disease -LRB- mean heart rate during scanning 86 bpm , Agatston score 259 -RRB- . a Thin-slab maximum-intensity projection shows stenosis of the distal right coronary artery near the origin of the posterior descending artery . This stenosis was rated significant -LRB- i.e. , > 50 % luminal diameter narrowing -RRB- by both readers . b Invasive coronary angiography in a right anterior oblique projection shows irregular luminal narrowing in the distal right coronary artery that was qualitatively graded as less than 50 % luminal diameter narrowing , resulting in a false positive diagnosis in DSCT coronary angiography On a per-segment analysis , overall sensitivity was 96.4 % -LRB- 54/56 ; 95 % CI : 87.7 -- 99.6 -RRB- , specificity was 97.5 % -LRB- 355/364 ; 95 % CI : 95.4 -- 98.9 -RRB- , positive predictive value was 85.7 % -LRB- 54/63 ; 95 % CI : 74.6 -- 93.3 -RRB- , and negative predictive value was 99.4 % -LRB- 355/357 ; 95 % CI : 98.0 -- 99.9 -RRB- . Table 2 summarizes demographic data , overall image quality , and diagnostic accuracy of DSCT . Table 2Demographic data , overall image quality , and diagnostic accuracy Mean heart rateAgatston score Total < 70 bpm ≥ 70 bpm < 400 ≥ 400No . of patients3017131515Age -LRB- years -RRB- 63.1 ± 11.363.2 ± 10.162.9 ± 13.362.8 ± 13.763.4 ± 8.9 Male/female24/615 / 29/410/514 / 1BMI -LRB- kg/m2 -RRB- 28.3 ± 3.928.9 ± 4.327.6 ± 3.528.1 ± 3.528.5 ± 4.4 Mean heart rate -LRB- bpm -RRB- 70.3 ± 14.259.7 ± 5.984.2 ± 8.470.6 ± 13.770.0 ± 15.1 Agatston score821 ± 904901 ± 991674 ± 78085 ± 1181,483 ± 893Overall image qualitya1 .68 ± 0.751.60 ± 0.731.81 ± 0.771.59 ± 0.751.79 ± 0.75 Score 147.4 % -LRB- 199/420 -RRB- 51.8 % -LRB- 131/245 -RRB- 38.9 % -LRB- 68/175 -RRB- 54.2 % -LRB- 116/214 -RRB- 40.3 % -LRB- 83/206 -RRB- Score 237.9 % -LRB- 159/420 -RRB- 32.4 % -LRB- 82/245 -RRB- 44.0 % -LRB- 77/175 -RRB- 35.5 % -LRB- 76/214 -RRB- 40.3 % -LRB- 83/206 -RRB- Score 313.3 % -LRB- 56/420 -RRB- 11.9 % -LRB- 30/245 -RRB- 14.9 % -LRB- 26/175 -RRB- 7.5 % -LRB- 16/214 -RRB- 19.4 % -LRB- 40/206 -RRB- Score 41.4 % -LRB- 6/420 -RRB- 0.8 % -LRB- 2/245 -RRB- 2.2 % -LRB- 4/175 -RRB- 2.8 % -LRB- 6/214 -RRB- -- Sensitivity96 .4 % -LRB- 54/56 -RRB- 97.2 % -LRB- 35/36 -RRB- 95.0 % -LRB- 19/20 -RRB- 100 % -LRB- 5/5 -RRB- 96.1 % -LRB- 49/51 -RRB- 95 % CI87 .7 -- 99.685.5 -- 99.975.1 -- 99.947.8 -- 10086.5 -- 99.5 Specificity97 .5 % -LRB- 355/364 -RRB- 97.1 % -LRB- 203/209 -RRB- 98.0 % -LRB- 152/155 -RRB- 99.5 % -LRB- 208/209 -RRB- 94.8 % -LRB- 147/155 -RRB- 95 % CI95 .4 -- 98.994.2 -- 98.894.5 -- 99.697.4 -- 10090.1 -- 97.8 PPV85 .7 % -LRB- 54/63 -RRB- 85.4 % -LRB- 35/41 -RRB- 86.4 % -LRB- 19/22 -RRB- 83.3 % -LRB- 5/6 -RRB- 86.0 % -LRB- 49/57 -RRB- 95 % CI74 .6 -- 93.370.8 -- 94.465.1 -- 97.135.9 -- 99.674.2 -- 93.7 NPV99 .4 % -LRB- 355/357 -RRB- 99.5 % -LRB- 203/204 -RRB- 98.8 % -LRB- 152/153 -RRB- 100 % -LRB- 208/208 -RRB- 98.7 % -LRB- 147/149 -RRB- 95 % CI98 .0 -- 99.997.3 -- 10096.4 -- 10098.2 -- 10095.2 -- 99.8 aApplied scores were 1 excellent -LRB- no artifacts -RRB- , 2 good -LRB- minor artifacts , good image quality -RRB- , 3 adequate -LRB- moderate artifacts , acceptable image quality -RRB- , and 4 not assessable -LRB- severe artifacts impairing image evaluation -RRB- . A score of 1 -- 3 was considered acceptable for diagnosis.BMI Body mass index , CI confidence interval , PPV positive predictive value , NPV negative predictive value On a per-patient analysis , sensitivity was 93.3 % -LRB- 14/15 ; 95 % CI : 68.1 -- 99.8 -RRB- , specificity was 100 % -LRB- 15/15 ; 95 % CI : 78.2 -- 100 -RRB- , positive predictive value was 100 % -LRB- 14/14 ; 95 % CI : 76.8 -- 100 -RRB- , and negative predictive value was 93.8 % -LRB- 15/16 ; 95 % CI : 69.8 -- 99.8 -RRB- . In both heart-rate subgroups , diagnostic accuracy for the assessment of coronary artery stenosis was similar and the rate of false ratings was comparable -LRB- one FN and six FP at heart rates < 70 bpm ; one FN and three FP at heart rates ≥ 70 bpm -RRB- . In contrast , the subgroup of patients with an Agatston score ≥ 400 included more false ratings -LRB- two FN and eight FP -RRB- than the subgroup of patients with an Agatston score < 400 -LRB- zero FN and one FP -RRB- . Consequently , sensitivity and specificity were worse in severely calcified vessels -LRB- see Table 2 -RRB- . Discussion Four main conclusions can be drawn from this study . First , DSCT coronary angiography provides a high diagnostic accuracy for the evaluation of CAD . Second , this high diagnostic performance of DSCT could be achieved in a patient population with extensive calcifications and in whom no heart rate control using beta blocker medication prior to CT was performed . Third , taking into account these circumstances , only six -LRB- 1.4 % -RRB- segments had to be excluded from data analysis , all in the distal part of the coronary artery tree with small vessel diameters . Fourth , false ratings were primarily due to severe vessel wall calcifications rather than motion artifacts . Temporal resolution better than 100 ms in combination with submillimeter isotropic spatial resolution and examination times no longer than 10 s are considered prerequisites for successful implementation of cardiac CT into routine clinical algorithms -LSB- 18 -RSB- . DSCT scanners with 0.33-s gantry rotation time and 32 × 0.6 mm collimation in combination with double z-sampling -LRB- i.e. , simultaneous acquisition of 64 overlapping 0.6-mm slices -RRB- fulfill these requirements . Early feasibility studies confirmed the technical capacity of DSCT to provide diagnostic image quality of coronary arteries in patients with high heart rates -LSB- 19 , 20 -RSB- . This study is , to the best of our knowledge , the first to demonstrate a high diagnostic accuracy of DSCT coronary angiography for the diagnosis of CAD in comparison to ICA . By including a patient population with a high prevalence of coronary calcification and without heart rate control during scanning , we found an overall sensitivity of 96.4 % and specificity of 97.5 % for the detection of significant coronary stenoses . These results are comparable to those previously reported with 64-slice CT ; however , beta-blocker administration for strict heart rate control was needed in those studies to compensate for motion artifacts . By including patients with heart rates up to 102 bpm , we found minor to moderate vessel wall blurring due to motion artifacts to be present at high heart rates ; however , only 1.4 % of all segments had to be excluded from analysis because they were non-diagnostic . Further confirmation of our preliminary results in larger patient populations may broaden the clinical indications for CT coronary angiography from a modality that is recommended for ruling-out CAD in patients with a low pre-test probability -LSB- 9 -RSB- to use in populations with intermediate - or even high pre-test probabilities of the disease . This might also include the implementation of CT coronary angiography as a tool for preoperative planning before cardiac bypass surgery -LSB- 25 -RSB- and as a gatekeeper for invasive angiography in patients referred for cardiac valve surgery -LSB- 26 -RSB- . Our patient population had a high prevalence of coronary wall calcification , with a mean Agatston score of 821 -- being higher than the 75 % percentile in an age - and gender-matched control population -LSB- 27 -RSB- . With 64-slice CT , Raff et al. -LSB- 2 -RSB- reported a considerable decline in diagnostic accuracy in patients with Agatston scores > 400 with a sensitivity of 93 % , a specificity of 67 % , and positive and negative predictive values of 93 and 67 % , respectively . Using the same cut-off Agatston score , we found a sensitivity of 96 % , a specificity of 95 % , and positive and negative predictive values of 86 and 99 % , respectively . Considering that the spatial resolution of DSCT is the same as that of the single-source 64-slice CT scanner , this apparent difference in calcification-dependency could indicate that the blooming artifact of severely calcified vessel walls may be sometimes superimposed by additional motion artifacts . We acknowledge the following study limitations . First , we included a relatively small group of only 30 patients . Certainly , future studies with larger patient populations are needed to confirm our first experience . Second , our study patients were a high pre-test probability population , which may have resulted in an overestimation of the ability of DSCT to detect and to rule-out stenoses . In particular the predictive value of positive and negative diagnostic tests is known to be strongly influenced by disease prevalence and pre-test probability . Third , we did not apply the multi-segment reconstruction mode , which possibly may further improve the image quality at elevated heart rates . Fourth , CT coronary angiography is associated with substantial irradiation to the patient . However , using the DSCT system allowed the variable use of ECG-pulsing for dose-saving purposes -LSB- 28 -RSB- in all of our patients . In the protocol applied in this study , the ECG-pulsing window width was chosen according to the mean heart rate during scanning , i.e. , a relatively narrow window width at low and a larger window width at higher heart rates . As previously performed for 64-slice CT -LSB- 17 , 29 -RSB- , studies analyzing optimum reconstruction intervals for DSCT coronary angiography are mandatory to reduce the width of the pulsing window and the applied radiation dose further . Finally , the ability to use the two x-ray tubes simultaneously with different voltages to improve plaque composition characterization -LSB- 30 -RSB- and thus potentially to improve the accuracy of stenosis detection has not been investigated . Conclusion First experience indicates that DSCT coronary angiography provides high diagnostic accuracy for assessment of CAD in a high pre-test probability population with extensive coronary calcifications and without heart rate control . Further studies are needed to confirm our results in appropriate clinical settings with larger patient populations .

O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

dual-source computed tomography
coronary stenosis


Local staging of rectal cancer : the current role of MRI With the advent of powerful gradient coil systems and high-resolution surface coils , magnetic resonance imaging -LRB- MRI -RRB- has recently extended its role in the staging of rectal cancer . MRI is superior to endorectal ultrasound , the most widely used staging modality in patients with rectal tumors , in that it visualizes not only the intestinal wall but also the surrounding pelvic anatomy . The crucial advantage of MRI is not that it enables exact T-staging but precise evaluation of the topographic relationship of a tumor to the mesorectal fascia . This fascia is the most important anatomic landmark for the feasibility of total mesorectal excision , which has evolved into the standard operative procedure for the resection of cancer located in the middle or lower third of the rectum . MRI is currently the only imaging modality that is highly accurate in predicting whether or not it is likely that a tumor-free margin can be achieved and thus provides important information for planning of an effective therapeutic strategy , especially in patients with advanced rectal cancer . Introduction Colorectal cancer is the third most common cancer worldwide -LSB- 1 , 2 -RSB- . In the United States , about 145,000 new cases and 56,000 deaths were estimated for 2005 -LSB- 1 -RSB- . In recent years , mortality rates have decreased due to major changes in therapeutic management , in particular the standardization of the operative procedure and the introduction of adjuvant and neoadjuvant therapy -LSB- 1 -RSB- . Colorectal cancer primarily develops from adenomatous polyps over a period of 10 -- 15 years , known as the adenoma-carcinoma sequence -LSB- 3 -RSB- . The incidence of polyps increases with age and the risk of malignant transformation of a polyp markedly increases with its diameter . The rate of malignant transformation is about 1 % for polyps less than 1 cm in diameter , but 10 % for larger ones -LSB- 4 , 5 -RSB- . Around 40 -- 50 % of colorectal cancers are located in the rectum . Rectal cancer is defined as a tumor whose aboral margin measured with the rigid rectoscope is 16 cm or less from the anocutaneous line . This distance serves to classify rectal cancer into tumors of the upper third -LRB- 12 -- 16 cm -RRB- , the middle third -LRB- 6 -- 12 cm -RRB- , and the lower third -LRB- < 6 cm -RRB- -LSB- 6 -RSB- according to the UICC . The mesorectal fascia is an important anatomic landmark for the diagnostic evaluation of local tumor extent -LSB- 7 -RSB- -LRB- Fig. 1b -RRB- . The fascia is a connective tissue sheath that encloses the rectum and the perirectal fatty tissue , including lymph nodes and lymphatic vessels down to the pelvic floor and acts as a natural barrier for tumor spread . The ability to visualize the mesorectal fascia on CT images has been described more than 20 years ago -LSB- 8 -RSB- . MRI currently is the most advanced staging modality able to depict the fascia and its relation to the tumor margins precisely . The following article will give an overview of the staging modalities currently used in rectal cancer staging , with an emphasis on the role of MRI and its significance for planning an effective therapeutical strategy for the individual patient . Fig. 1a Axial T2-weighted FSE -LRB- TSE -RRB- sequence of the pelvis depicting the layers of the rectal wall . The mucosa and submucosa can be visualized as a relatively hyperintense band -LRB- arrows -RRB- . The hypointense line -LRB- arrowheads -RRB- represents the muscularis propria . b Axial T2-weighted FSE -LRB- TSE -RRB- sequence . The mesorectal fascia can be visualized as a thin line -LRB- arrowheads -RRB- , enveloping the mesorectal compartment , containing the rectum , mesorectal fat , blood vessels , lymphatic vessels and nodes Therapeutic options Surgery The anatomic position of the rectum in the true pelvis and its vicinity to adjacent anatomy , in particular the sphincter muscles , poses a challenge for the surgeon regardless of the surgical technique used . Surgical treatment of rectal cancer is a difficult balancing act between minimizing the risk of local recurrence and the preservation of anorectal and genitourinary function . Total mesorectal excision -LRB- TME -RRB- The introduction of standardized TME -LSB- 9 -RSB- has considerably improved prognosis in patients with cancer located in the middle or lower third of the rectum . Using this operative technique , the rectum is resected together with all surrounding lymphatic pathways , lymph nodes , mesorectal fatty tissue , and the mesorectal fascia while the parietal pelvis fascia and the pelvic splanchnic nerves -LRB- nervi erigentes -RRB- are spared . The widespread introduction of TME has markedly reduced the rate of non-continence-preserving abdominoperineal operations for rectal cancer . Local excision is an option in patients with very small , well to moderately differentiated tumors that are confined to the mucosa and submucosa -LSB- 10 -RSB- . Techniques used for local excision are transanal surgical tumor removal and endoscopic microsurgical tumor ablation . Only a few patients are candidates for local excision -LRB- about 5 % -RRB- and these must be selected with great care . Circumferential resection margin -LRB- CRM -RRB- and local recurrence The local recurrence rate after surgery performed with curative intent ranges between 3 % and 32 % -LSB- 11 -RSB- . For TME , some studies report local recurrence rates that are markedly below 10 % -LSB- 12 -- 14 -RSB- . Lateral circumferential tumor extent is a much more important prognostic factor for local recurrence than longitudinal tumor extent . Incomplete resection of the lateral tumor margins is now considered the most important cause of local recurrence -LSB- 15 -- 17 -RSB- . In a study by Quirke et al. -LSB- 15 -RSB- , 83 % of the patients with a positive CRM had local tumor recurrence . Hence , the topographic relationship of the tumor to the mesorectal fascia that serves as a natural barrier and anatomic landmark for TME is the most important criterion in local tumor staging for therapeutic decision making . Adjuvant/neoadjuvant therapy The aims of adjuvant or neoadjuvant therapy are to enable or facilitate total tumor resection even in advanced disease , to prevent local tumor recurrence , and to minimize the risk of distant metastases . Adjuvant or neoadjuvant therapy leads to downstaging of the tumor -LSB- 18 , 19 -RSB- in terms of its T and N stages , and 20 % of patients even show complete tumor regression -LRB- sterilization -RRB- -LSB- 20 -RSB- . The timing of adjuvant or neoadjuvant therapy is still a matter of debate . Based on the results of two large studies -LSB- 21 , 22 -RSB- , preoperative radiotherapy alone or combined radiochemotherapy is the preferred option for tumors of the middle or lower rectum in Europe . One of these studies , performed in Scandinavia -LSB- 21 -RSB- , showed that a short cycle of preoperative radiotherapy reduces the local recurrence rate from 27 % to 11 % . The second study showed that even patients who underwent TME , which already has a lower recurrence rate than other operative approaches , benefit from preoperative radiotherapy -LSB- 22 -RSB- . Preoperative irradiation significantly reduced local recurrence compared to the group treated by TME only . In the United States , adjuvant therapy consisting of combined postoperative radiochemotherapy is favored for patients with T3 and/or N1 tumors . -LSB- 23 -RSB- . Local tumor staging Tumor staging is crucial for the prognosis and planning of therapy in the individual patient and aims at precisely determining the extent of the tumor as a basis for deciding whether surgery alone or surgery in combination with neoadjuvant therapy is the most suitable strategy . Of course , it is of great importance to avoid overtreatment or undertreatment of the patient . To reach a high level of accuracy in rectal cancer staging and to develop an adequate individual strategy for therapy , it is indispensable to establish a multidisciplinary team -LSB- 24 -RSB- . Rectal cancer staging is now mostly based on the TNM and UICC staging systems -LSB- 6 -RSB- -LRB- Tables 1 , 2 -RRB- , which have largely replaced the older Dukes classification . The most important anatomic structure on which staging is based using these staging systems is the lamina muscularis propria . While T1 rectal carcinomas are confined to the mucosa and submucosa , T2 tumors invade the muscularis propria -LRB- Figs. 2a -- c and 3 -RRB- . A T3 cancer is defined as a tumor extending beyond the lamina muscularis propria -LRB- Figs. 4 , 5 -RRB- . However , none of the staging systems takes into account the fact that the T3 tumors are a very heterogeneous group , comprising tumors that just barely extend beyond the lamina muscularis propria as well as tumors that extend to or invade the mesorectal fascia -LRB- Figs. 4 , 5 -RRB- without further subclassification . The therapeutically important topographic relationship of the lateral tumor margins to the mesorectal fascia is not taken into consideration . An adequate , state-of-the-art staging classification should be able to precisely determine this relationship and to predict whether a tumor-free CRM is likely to be achieved or not . In this way one would be able to differentiate patients with minimal mesorectal infiltration in whom neoadjuvant therapy is not mandatory from patients who would definitely benefit from neoadjuvant therapy because the mesorectal fascia is infiltrated or at risk . T4 rectal cancers are defined as tumors , that reach the peritoneal surface or adjacent organs -LRB- Figs. 6a , b , 7 , 8 -RRB- . Table 1TNM classification for colorectal cancerTypeDescriptionT1Tumor involves submucosaT2Tumor involves muscularis propriaT3Tumor beyond muscularis propriaT4Tumor reaches peritoneal surface or invades adjacent organN0No involved nodesN1Up to three perirectal/colic nodesN2Four or more perirectal/colic nodesTable 2UICC staging of rectal carcinomaStageDescriptionStage 0TisN0M0Stage IT1N0M0T2N0M0Stage IIAT3N0M0 BT4N0M0Stage IIIAT1 , T2N1M0 BT3 , T4N1M0 CEvery TN2M0Stage IVEvery TEvery NM1Fig . 2a Paraxial T2-weighted FSE -LRB- TSE -RRB- sequence . T1/2 rectal cancer . The relatively hyperintense intraluminal tumor -LRB- arrowhead -RRB- is confined to the rectal wall . Tumor invasion of the mesorectum is not visible . b Paraxial 3D-MPR and c intraluminal -LRB- virtual endoscopy -RRB- CT reconstuctions after rectal insufflation of CO2 showing the same tumor as aFig . 3Paraxial T2-weighted FSE -LRB- TSE -RRB- sequence . Tumor of the rectal wall . Fibrous strands into the mesorectum represent desmoplastic reaction -LRB- arrow -RRB- . A differention between desmoplastic reaction and tumor infiltration of the mesorectum can be difficultFig . 4Paraxial T2 weighted FSE -LRB- TSE -RRB- sequence . A T3 rectal cancer breached through the muscularis propria -LRB- arrow -RRB- and invades the mesorectum . The tumor does not reach the mesorectal fascia -LRB- arrowheads -RRB- . A tumor-free CRM can be expectedFig . 5Paraxial T2-weighted FSE -LRB- TSE -RRB- sequence . A T3 rectal cancer widely invades the mesorectum . A tumor deposit -LRB- arrow -RRB- is located directly adjacent to the mesorectal fascia -LRB- arrowhead -RRB- . A tumor-free resection margin can not be predictedFig . 6a Paraxial T2-weighted FSE -LRB- TSE -RRB- sequence and b sagittal T2-weighted FSE -LRB- TSE -RRB- sequence of a T4 cancer located in the upper third of the rectum invading the uterus -LRB- arrows -RRB- Fig. 7Paraxial T2-weighted FSE -LRB- TSE -RRB- sequence of a low T4 rectal cancer with infiltration of the levator ani muscle -LRB- arrow -RRB- Fig. 8Recurrent rectal cancer . Paraxial T1-weighted SE sequence with fat suppression after i.v. apllication of gadopentetate-dimelglumine at a dosage of 0.2 mmol/kg body weight . The large extraluminal tumor shows central necrosis -LRB- arrowhead -RRB- and reaches the right pelvic wall Staging modalities Endorectal ultrasound -LRB- EUS -RRB- EUS is the oldest and most widely used imaging technique for evaluating the local extent of rectal cancer . EUS depicts the anatomic layers of the rectal wall with a high degree of accuracy and thus enables precise determination of the tumor extent in relation to the different wall layers . Reported accuracy rates of transrectal ultrasound in assessing the T stage are in the range of 69 -- 97 % -LSB- 25 -- 35 -RSB- . EUS is most suitable for evaluating early rectal cancer while it is limited in assessing more advanced tumors . Although EUS allows the identification of transmural tumor growth , exact determination of the circumferential tumor spread and -- even more important -- depiction of the relation between the edges of the tumor and the mesorectal fascia is often not possible due to the limited scan depth caused by the high frequencies used . Moreover , the accuracy varies widely with the examiner 's experience -LSB- 28 , 36 -RSB- . Computed tomography -LRB- CT -RRB- Most older studies report rather low accuracy rates of only 52 -- 70 % -LSB- 32 , 37 -- 41 -RSB- for T-staging by CT. . It is remarkable that accuracy levels reported in studies including less advanced tumors were considerably lower compared with those including only advanced tumor stages . The poor accuracy of CT in the staging of superficial tumors is mainly attributable to the fact that these studies used conventional CT protocols with low spatial and contrast resolution . The accuracy has since been improved by the advent of the multislice technique -LRB- MSCT -RRB- . In a study of 92 patients by Kulinna et al. -LSB- 42 -RSB- , T-staging using MSCT was found to have an accuracy of 86 % , while Filippone et al. -LSB- 43 -RSB- found an accuracy of 83 % in a study of 41 patients . If one takes into account that four-row CT scanners were used in these studies , it is evident that further improvement is to be expected from state-of-the-art CT scanners with up to 64 detector rows that are already in use today . Hence , the role of MSCT in the local staging of rectal cancer remains to be defined . CT is superior to both EUS and MRI in that the scan typically covers the entire abdomen and pelvis and thus also allows evaluation of the liver , the most important target organ of hematogenic metastatic spread of rectal cancer . MRI It is undisputed that MRI is the imaging modality with the highest soft-tissue contrast . This is why MRI is also used for staging rectal cancer . However , initial results with MRI were disappointing , with accuracies in T-staging reported in older studies ranging between 58 and 74 % -LSB- 39 , 44 -- 46 -RSB- . These rather poor results are primarily due to the poor spatial resolution achieved with the whole-body coil systems used in these studies . When endorectal coils are used , MRI has similar accuracies as EUS -LSB- 31 , 47 -- 49 -RSB- . MRI using endorectal coil systems is comparable to EUS in that it allows highly accurate differentiation of the layers of the intestinal wall . However , endorectal coils also have a number of disadvantages . As with EUS , the field of view -LRB- FOV -RRB- is rather small and only allows adequate evaluation of early stages of rectal cancer because the evaluation of surrounding pelvic anatomy is limited . In patients with advanced tumors , insertion of the coil system may be impossible or is very painful . Another disadvantage is the high cost of endorectal coils , which are usually disposable . The advent of powerful gradient systems and , above all , the development of high-resolution phased array surface coil systems in recent years brought the breakthrough in the staging of rectal cancer by MRI . The use of these phased-array surface coils combines a very high spatial resolution with a large FOV that allows not only detailed evaluation of the intestinal wall but also depicts surrounding anatomy including the mesorectal fascia . Imaging technique Rectal cancer staging by MRI is rather fast and straightforward . No special patient preparation is required . Some authors recommend administration of a positive or negative enteral contrast medium , but this seems not to be necessary as suggested by current data in the literature . A study published only recently even indicated that rectal distension significantly reduces the distance between the rectal wall and the mesorectal fascia and that this might impact on the ability of MRI to predict accurately the distance between the tumor and the potential resection margin -LSB- 50 -RSB- . At our department , we administer a spasmolytic agent -LRB- butylscopolamine -RRB- at a dose of 20 -- 40 mg to prevent artifacts caused by peristalsis of the small intestine and to distend the sigmoid and rectum . The agent has a short half-life and is therefore injected intramuscularly immediately before MRI . For efficient planning of the pulse sequences to be employed , the radiologist performing the examination should beforehand obtain information about the approximate tumor localization -LRB- distance from anocutaneous line in cm -RRB- from the referring surgeon and ask the patient about any previous surgery or diseases of the pelvic organs . The patient is positioned comfortably on the back and a phased-array surface coil is placed on the pelvis in such a way that the lower edge of the coil comes to lie well below the pubic bone . The coil is kept in place with belts and the patient is then advanced head-first into the bore of the magnet . Following the usual localizer scans , a sagittal T2-weighted half-Fourier single shot turbo spin-echo -LRB- SSFSE , HASTE -RRB- sequence with a large field of view -LRB- FOV -RRB- should be acquired to obtain an overview and for planning of the subsequent sequences -LRB- e.g. TR ∞ , TE 62 ms , slice thickness 5 mm , FOV 255 × 340 mm , matrix size 116 × 256 , voxel size 2.2 × 1.3 × 5 mm -RRB- . Precise tumor localization is then achieved with an axial T2-weighted fast spin-echo -LRB- FSE -RRB- or turbo spin-echo -LRB- TSE -RRB- sequence with a large FOV and a slice thickness of 5 mm -LRB- e.g. TR 4,170 ms , TE 98 ms , FOV 300 × 220 mm , matrix 282 × 512 , voxel size 0.8 × 0.6 × 5 mm -RRB- . At the core of the examination is a high-resolution T2-weighted TSE sequence with a small FOV and a slice thickness of 3 mm -LRB- e.g. TR 3,570 ms , TE 68 ms , FOV 180 × 180 mm , matrix 179 × 256 , voxel size 1.0 × 0.7 × 3 mm -RRB- . It is mandatory to place the slices perpendicular to the longitudinal axis of the tumor or the intestinal lumen in the vicinity of the tumor . With this sequence , it is possible to precisely evaluate the tumor and its relationship to the intestinal wall , mesorectal fascia , the pelvic organs , and possibly also to the peritoneal fold . Moreover , mesorectal lymph nodes in the immediate vicinity of the tumor can be evaluated . For visualization of more distant lymph nodes in our institution a T1 to proton-density-weighted two-dimensional -LRB- 2D -RRB- TSE sequence with a short echo train length -LRB- e.g. 3 or 5 -RRB- in axial orientation -LRB- e.g. TR 1,980 ms , TE 10 ms , slice thickness 5 mm , FOV 300 × 225 mm , matrix 219 × 512 , voxel size 1 × 0.6 × 5 mm -RRB- , which covers the entire area up to the aortic bifurcation is used . Alternatively , a T1-weighted 3D gradient-echo sequence can be used for this purpose , allowing for the reconstruction of thinner slices . Possible infiltration of the anal sphincter muscles in patients with low tumors is evaluated using a coronal T2-weighted FSE -LRB- TSE -RRB- sequence -LRB- e.g. TR 3,570 ms , TE 68 ms , FOV 180 × 180 , matrix 179 × 256 , voxel size 1.0 × 0.7 × 3 mm -RRB- positioned parallel to the longitudinal axis of the anal canal . Current data in the literature suggests that intravenous contrast medium administration does not improve staging of rectal tumors by MRI -LSB- 51 , 52 -RSB- . Since differentiation with the T2-weighted sequences is based on the contrast between the high-signal-intensity mesorectal fatty tissue and the rather low signal intensity of the tumor , spectral fat suppression techniques are not needed . The duration of the MRI protocol as just outlined is about 25 -- 30 min , including planning . T-staging Although the introduction of phased-array coil systems has improved the accuracy of MRI in staging rectal cancer , even more recent studies report accuracies of only 67 -- 86 % for T-staging -LSB- 53 -- 56 -RSB- . These disappointing results are primarily due to the poor differentiation of T1/2 cancer from so-called borderline T3 cancer , where it is often not possible to distinguish true mesorectal tumor invasion from desmoplastic reactions -LRB- Fig. 3 -RRB- -LSB- 49 , 54 , 57 -RSB- . Desmoplastic reactions are reactive tissue alterations which often occur in the immediate surrounding of tumors , most frequently resulting in fibrotic extensions that may contain tumor cells or not . The failure to differentiate between desmoplastic reactions and tumor growth is not specific to MRI but is also a well-known problem in rectal cancer staging with EUS -LSB- 27 -RSB- . Clinically and therapeutically , however , this differentiation is of minor importance . As already mentioned , it is much more important to precisely describe the relationship of the tumor to the mesorectal fascia , representing the anticipated resection plane for TME in order to assess the likelihood of a tumor-free CRM . Several recent studies have confirmed that MRI is highly suited to provide this information -LSB- 54 , 57 -- 60 -RSB- . In a study of 43 patients , Bissett et al. -LSB- 59 -RSB- found good agreement between preoperative MRI and histopathology with regard to the demonstration of tumor penetration through the mesorectal fascia -LRB- accuracy : 95 % -RRB- . These results are underlined by the studies of Beets-Tan et al. -LSB- 54 , 61 -RSB- , who investigated 76 patients and likewise found preoperative MRI to be highly accurate in assessment of the CRM . The agreement was 100 % in T4 tumors , and 97 % and 93 % for both readers in tumors with a histologically determined tumor-free CRM > 10 mm . Regression analysis for histologically determined margins of 1 -- 10 mm demonstrated that a tumor-free resection margin of 2 mm was predicted with an accuracy of 97 % if the distance between tumor and mesorectal fascia measured by MRI was at least 6 mm . It is noteworthy that this study likewise showed only moderate results with regard to T-staging -LRB- accuracy of 83 % and 67 % for the two readers -RRB- -LSB- 54 , 61 -RSB- . In a study of 98 patients published by Brown and co-workers in 2003 , the agreement between MRI and histology in assessment of the CRM was 92 % -LSB- 60 -RSB- . These figures indicate that MRI allows accurate prediction of the CRM status after resection . The expected CRM can be described as involved if tumor invasion of the mesorectal fascia is visible or the tumor has a proximity of 1 mm or less to the mesorectal fascia . A tumor-free CRM can be assumed with a high degree of accuracy if the shortest distance from the maximum tumor extension , a mesorectal tumor deposit or a suspect lymph node in the mesorectum is more than 6 mm -LSB- 54 -RSB- . The role of tumors that extend towards the mesorectal fascia to a distance of less than 5 mm on MR images remains controversial . The study by Brown et al. -LSB- 60 -RSB- also suggests that other important prognostic factors besides the CRM are the infiltration of extramural veins and possible infiltration of the peritoneal fold and that these can also be identified by preoperative MRI . A study by Oberholzer and co-workers published in 2005 has shown that parallel imaging techniques do not compromise diagnostic accuracy with regard to the assessment of the CRM , but can considerable shorten the examination -LSB- 62 -RSB- . N-staging Identification of metastatic lymph nodes is the greatest challenge in preoperative staging of rectal cancer , regardless of the modality used -LRB- Figs. 9 , 10 , 11 -RRB- . Exact staging is important because the number of metastatic nodes has been shown to affect the prognosis -LSB- 63 -RSB- . Involvement of lymph nodes in the vicinity of the mesorectal fascia is associated with a higher risk of local recurrence -LSB- 16 -RSB- . In patients with metastatic nodes outside the mesorectal fascia , extended lymph node resection with additional removal of the internal iliac nodes becomes necessary -LSB- 64 -RSB- . This lymph node group is not removed when regular TME is performed . A special problem associated with identifying lymphatic involvement in rectal cancer is that lymph node size is not a reliable criterion for metastatic involvement because micrometastasis in normal-sized lymph nodes is common -LSB- 65 , 66 -RSB- . Fig. 9Sagittal T2-weighted FSE -LRB- TSE -RRB- sequence . The enlarged mesorectal lymph node -LRB- arrow -RRB- shows heterogenous signal intensity indicating tumor invasionFig . 10Axial PD-weighted FSE -LRB- TSE -RRB- sequence . A large lymph node metastasis -LRB- asterisk -RRB- located below the aortic bifurcation in a patient with rectal cancerFig . 11Axial T2-weighted FSE -LRB- TSE -RRB- sequence . Inguinal lymph node metastases -LRB- arrows -RRB- in a patient with low rectal cancer The accuracy rates reported in the literature for N-staging by the different imaging modalities vary widely -LRB- EUS : 61 -- 80 % -LSB- 10 , 25 , 26 , 30 -- 32 , 34 , 35 , 37 , 67 -RSB- , CT : 56 -- 79 % -LSB- 32 , 39 , 68 , 69 -RSB- , MRI : 57 -- 85 % -LSB- 32 , 39 , 47 , 53 , 55 , 60 -RSB- . In a current meta-analysis including 84 studies , Lahaye et al. -LSB- 70 -RSB- found EUS to be slightly superior in assessing nodal status , but there were altogether no significant differences between the three staging modalities investigated . In summary , these results suggest that none of the imaging procedures currently in use enables reliable detection of metastatic lymph nodes . In their study of MRI with histologic correlation , Brown et al. -LSB- 71 -RSB- identified an irregular contour and inhomogeneous signal to be the most reliable MRI criteria for lymph node metastasis -LRB- Fig. 9 -RRB- . Future perspectives USPIO A new promising approach to detect metastatic lymph nodes by MRI is imaging in combination with ultrasmall superparamagnetic iron oxide particles -LRB- USPIO -RRB- as a contrast medium for systemic MR lymphography -LRB- Fig. 12a , b -RRB- . Following intravenous administration , the particles are phagocytozed by nodal macrophages and , due to susceptibility effects , cause a signal decrease in normal or reactively changed lymph nodes on T2 - and T2 * - weighted images , which are usually acquired 24 h after administration of USPIO -LSB- 72 -RSB- . USPIO agents are currently under clinical evaluation and are not yet clinically available . Initial results of a study investigating this new approach in mesorectal lymph nodes are promising -LSB- 73 -RSB- . Further studies are needed to show whether USPIO can significantly improve lymph node staging by MRI . Fig. 12a Axial PD-weighted sequence of the pelvis . Two small lymph nodes are visible adjacent to the iliac vessels -LRB- arrows -RRB- . b Axial T2 * - weighted gradient echo sequence acquired 24 hours after i.v. infusion of USPIO -LRB- Sinerem -RRB- . The two lymph nodes -LRB- arrows -RRB- show homogenous signal decrease indicating normal lymphatic tissue . As USPIO agents are currently under clinical evaluation and are not yet clinically available , this image was acquired during a clinical trial Whole-body MRI The recent introduction of powerful whole-body MRI systems enables imaging of the whole body in a single session through repeated table movement . Several studies have already demonstrated the benefit of this approach for a variety of diagnostic queries in oncologic patients -LSB- 74 -- 77 -RSB- . This technique may also be used for rectal cancer staging in the future and allow local staging and whole-body staging in a single session . In this way it would become possible to also evaluate the liver as the primary target organ of hematogenic spread of rectal cancer . The potential of parallel imaging to shorten the examination that has already been mentioned would be of particular significance in this respect -LSB- 62 -RSB- . Diffusion/perfusion-weighted MRI and PET It has long been known that the pathophysiology and aggressiveness of a tumor are determined not only by the macroscopic tumor extent but also by other factors such as tumor microcirculation and angiogenesis . Several studies have shown the potential of diffusion - or perfusion-weighted imaging to indirectly determine these factors and to thus predict the response to adjuvant or neoadjuvant therapy -LSB- 78 -- 81 -RSB- . However , extensive further research is necessary before the routine clinical use of these new techniques . Recent studies have indicated that PET is able to predict response to neoadjuvant treatment of locally advanced rectal cancer with a high degree of accuracy -LSB- 82 -RSB- . Conclusion The advances that have been made in the treatment of rectal cancer in recent years and that have considerably improved the prognosis of affected patients rely on differentiated pretherapeutic tumor staging . Despite its known limitations in T-staging , MRI is currently the only imaging modality that enables highly accurate evaluation of the topographic relationship between lateral tumor extent and the mesorectal fascia and to thus make a prediction about the CRM . In this way it is possible to carefully select those patients who will benefit from neoadjuvant therapy and to avoid overtreatment or undertreatment .

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O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B I B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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