Presentation on theme: "Diagnostic Backgrounder"— Presentation transcript:
1 Diagnostic Backgrounder CARDIAC MRIDiagnostic BackgrounderNOTE: These slides are for use in educational oral presentations only. If any published figures/tables from these slides areto be used for another purpose (e.g. in printed materials), it is the individual’s responsibility to apply for the relevant permission. Specific local use requires local approval
2 Outline Introduction to iron overload Assessing cardiac iron loading echocardiographycardiac MRICardiac MRI in practicepreparation of the patientacquisition of the imageanalysis of the dataExcel spreadsheetThalassaemiaTools (CMRtools)cmr42FerriScanMRmapMATLABSummaryMRI = magnetic resonance imaging.
4 Introduction to iron overload Iron overload is common in patients who require intermittent or regular blood transfusions to treat anaemia and associated conditionsit may be exacerbated in some conditions by excess gastrointestinal absorption of ironIron overload can lead to considerable morbidity and mortality1Excess iron is deposited in major organs, resulting in organ damagethe organs that are at risk of damage due to iron overload include the liver, heart, pancreas, thyroid, pituitary gland, and other endocrine organs2,31Ladis V, et al. Ann NY Acad Sci. 2005;1054: Gabutti V, Piga A. Acta Haematol. 1996;95: Olivieri NF. N Engl J Med. 1999;341:
5 Importance of analysing cardiac iron In β-thalassaemia major, cardiac failure and arrhythmia are risk factors for mortality1signs of myocardial damage due to iron overload: arrhythmia, cardiomegaly, heart failure, and pericarditis2heart failure has been a major cause of death in β-thalassaemia patients in the past (50–70%)1,3In MDS, the results of studies are less comprehensiblethe reported proportion of MDS patients with cardiac iron overload is inconsistent; from high to only a small proportion of MDS patients4–7cardiac iron overload occurs later than does liver iron overload4,7,8however, cardiac iron overload can have serious clinical consequences in MDS patients1Borgna-Pignatti C, et al. Haematologica. 2004;89: Gabutti V, Piga A. Acta Haematol. 1996;95: Modell B, et al. Lancet. 2000;355: Jensen PD, et al. Blood. 2003;101:5Chacko J, et al. Br J Haematol. 2007;138: Konen E, et al. Am J Hematol. 2007;82:7Di Tucci AA, et al. Haematologica. 2008;93: Buja LM, Roberts WC. Am J Med. 1971;51:
6 Importance of analysing cardiac iron (cont.) In 2010, the overall mortality rate of β-thalassaemia major patients in the UK was substantially lower than a decade ago (1.65 vs 4.3 per 1,000 patient years)1,2due to improved monitoring and management of iron overload over the last decade, 77% of patients have normal cardiac T2*1cardiac iron overload is no longer the leading cause of death in this population16017237102030405070BaselineLatest follow-upPatients (%)p < 0.001p < 0.001cT2* ≤ 20 mscT2* < 10 mscT2* = cardiac T2*.1Thomas AS, et al. Blood. 2010;116:[abstract 1011]. 2Modell B, et al. Lancet. 2000;355:
7 Cardiac T2*: Overview of correlations with other measurements Transfusion duration† ↑1Ventricular dysfunction ↑1-3Arrhythmia and heart failure ↑4T2*↓Need for cardiac medication↑1-2APFR↓ EPFR:APFR↑5SF and LIC1-3Weak or no correlation†For thalassaemia, but not sickle cell.APFR = atrial peak filling rate; EPFR = early peak filling rate; LIC = liver iron concentration; SF = serum ferritin.1Wood JC, et al. Blood. 2004;103: Anderson LJ, et al. Eur Heart J. 2001;22: Tanner MA, et al. J Cardiovasc Magn Reson. 2006;8: Kirk P, et al. Circulation. 2009;120:5Westwood MA, et al. J Magn Reson Imaging. 2005;22:
8 Cardiac T2*: Relationship with LVEF 90Normal T2* range80Normal LVEF range7060Cardiac T2* value of 37 ms in a normal heart50LVEF (%)40302010Cardiac T2* value of 4 ms in a significantly iron-overloaded heart102030405060708090100Cardiac T2* (ms)Myocardial T2* values < 20 ms are associated with a progressive and significant decline in LVEFLVEF = left-ventricular ejection fraction.Anderson LJ, et al. Eur Heart J. 2001;22:
9 Cardiac T2*: Relationship with cardiac failure and arrhythmia 0.6< 6 ms0.150.100.050.200.250.300.5< 10 ms0.46–8 msProportion of patients developing cardiac failureProportion of patients with arrhythmia0.30.28–10 ms10–20 ms0.1> 20 ms> 10 ms6012018024030036060120180240300360Follow-up time (days)Follow-up time (days)T2* < 10 ms: relative risk 159 (p < 0.001) T2* < 6 ms: relative risk 268 (p < 0.001)T2* < 20 ms: relative risk 4.6 (p < 0.001) T2* < 6 ms: relative risk 8.65 (p < 0.001)Low myocardial T2* predicts a high risk of developing cardiac failure and arrhythmiaKirk P, et al. Circulation. 2009;120:
13 Assessing cardiac iron loading: Echocardiography ProsConsReadily available1Relatively inexpensive1Does not detect early damage2Echocardiographic diastolic function parameters correlate poorly with LVEF and T2*1Cannot directly or indirectly quantify cardiac iron levelsEF = ejection fraction.1Leonardi B, et al. JACC Cardiovasc Imaging. 2008;1: Hoffbrand AV. Eur Heart J. 2001;22:
15 MRI: A non-invasive diagnostic tool Indirectly measures levels of iron in the heartMRI measures longitudinal (T1) and transverse (T2) relaxation times of the protonsiron deposition disrupts the homogeneous magnetic field and shortens T1 and T2 times in a concentration-dependent mannerProtonsMagnetic fieldRF/spin echo/gradient echoIronEcho signal → T1, T2Signal processingRF = radio-frequency.1Wood JC, Ghugre N. Hemoglobin. 2008;32: Wood JC, et al. Circulation. 2005;112:3Wang ZJ, et al. Radiology. 2005;234: Ghugre NR, et al. Magn Reson Med. 2006;56:681-6.
16 MRI: A non-invasive diagnostic tool (cont.) ProtonsIf a spin-echo sequence is used, the relaxation time is T2If a gradient-echo sequence is used, it is T2*Cardiac MRI methodsgradient-echo T2* MRI: most used in clinical practicespin-echo T2 MRI: less useful (motion artefacts common due to characteristics of the heart)Magnetic fieldMost used in clinical practice:Gradient echoSpin echoImage acquired at different TEsImage acquired at different TEsExcel or softwareExcel or softwareIf a spin-echo sequence is used, the relaxation time is T2If a gradient-echo sequence is used, it is T2*T2* [ms}T2* [ms}R2* [Hz]= 1,000/T2*R2* [Hz]= 1,000/T2*TE = echo time.Adapted from Wood JC, Ghugre N. Hemoglobin. 2008;32:85-96.
17 Assessing cardiac iron loading: Cardiac MRI Advantages of MRIDisadvantages of MRINon- invasiveRapidly assesses iron content in the septum of the heartRelative iron burden can be reproducibly estimatedFunctional parameters can be examined concurrently (e.g. LVEF)Iron status of liver and heart can be assessed in parallelAllows longitudinal follow-upGood correlation with morbidity and mortality outcomesIndirect measurement of cardiac ironRequires MRI imager with dedicated imaging methodRelatively expensive and varied availability.
18 FAQ: Cardiac MRI What are sequences? Sequences are a set of radio-frequency and gradient pulses (slight tilts in the magnetization curves of the scanner) generated repeatedly during the scan, which produce echoes with varied amplitudes and shapes that will define the MR imageWhat is gradient echo?A gradient-echo sequence is obtained after 2 gradient impulses are applied to the body, resulting in a signal echo that is read by the coils. In these sequences, the spins are not refocused and, therefore, are subject to local inhomogeneities, with a more rapid decay curve. For gradient-echo pulse sequences, the T2* relaxation times (which reflect these inhomogeneities) on the signal are more significant1Image from Ridgway JP. J Cardiovasc Magn Reson. 2010;12:71.
19 Gradient relaxometry (T2. , R2 Gradient relaxometry (T2*, R2*) is the method for analysing cardiac iron levelsT2* (gradient echo)T2 (spin echo)ProsGreater sensitivity to iron deposition2Shorter acquisition time1Less affected by motion artefacts3More readily available3Easier to perform4Good reproducibility5Less affected by susceptibility artefacts1, due to metal implants, air–tissue interfaces, proximity to cardiac veinsConsMore sensitive to static magnetic field inhomogeneity1Noise, motion, and blood artefacts can complicate analysis (particularly in heavily iron-loaded hearts)7Lack of sensitivity6Motion artefacts6Poor signal-to-background noise ratios at longer TEs6Longer acquisition time11Guo H, et al. J Magn Reson Imaging. 2009;30: Anderson LJ, et al. Eur Heart J. 2001;22: Wood JC, Noetzli L. Ann N Y Acad Sci. 2010;1202: Wood JC, Ghugre N. Hemoglobin. 2008;32: Westwood M, et al. J Magn Reson Imaging. 2003;18:33-9.6Hoffbrand AV. Eur Heart J. 2001;22: He T, et al. Magn Reson Med. 2008;60:
20 Gradient relaxometry (T2. , R2 Gradient relaxometry (T2*, R2*) can conveniently measure cardiac and liver ironCardiac MRILiver MRI302468101214Hankins, et al.2520Wood, et al.HIC (mg Fe/g of dry weight liver)15[Fe] (mg/g dry wt)10Anderson, et al.R2 =51002003004002004006008001000Cardiac R2* (Hz)Liver R2* (Hz)Cardiac and liver iron can be assessed together conveniently by gradient echo during the a single MRI measurement.HIC = hepatic iron concentrationCarpenter JP, et al. J Cardiovasc Magn Reson. 2009;11 Suppl 1:P224.Hankins et al Blood. 2009;113:
21 Cardiac T2* MRI is usually measured in the septum of the heart Heart with normal iron levelsT2* = 22.8 ms or R2* = 43.9 HzHeart with severe iron overloadT2* = 5.2 ms or R2* = 192 HzImages courtesy of Dr J. de Lara Fernandes.
22 What is R2*?Conversion from T2* to R2* is a simple mathematical calculation: R2* = 1,000/T2*Level of cardiac iron overloadT2*, msR2*, HzNormal 201< 50Mild, moderate10–20150–100Severe< 102> 100These values are only applicable to 1.5 T scanners11Anderson LJ, et al. Eur Heart J. 2001;22: Kirk P, et al. Circulation. 2009;120:
23 Why should the data be presented as R2* and not T2*? Seven whole hearts from patients with transfusion-dependent anaemias were assessed by histology and cardiac MRI24681012142468101214[Fe] (mg/g dry wt)[Fe] (mg/g dry wt)R2 = 0.949R2 =10203040506070100200300400Cardiac T2* (ms)Cardiac R2* (Hz)R2* has a linear relationship with tissue iron concentration, which simplifies the interpretation of data and allows comparison of changes over timeCarpenter JP, et al. J Cardiovasc Magn Reson. 2009;11 Suppl 1:P224.
24 Why should the data be presented as R2* and not T2*? (cont.) The relationship between cardiac T2*/R2* and LVEFHockey stick effect?Or a more gradual relationship?100806040209080706050LVEF (%)LVEF (%)4030201010203040506070809010050100150200250Heart T2* (ms)R2* (s–1)R2* allows demonstration of cardiac risk in a more gradual wayAnderson LJ, et al. Eur Heart J. 2001;22:
25 Why should the data be presented as R2* and not T2*? (cont.) Standard errors on a single measurement are approximately constant with R2*, but are non-uniform with T2*Transform to R2*60120501004080T2* first measurement (ms)30R2* first measurement (s–1)602040102010203040506020406080100120T2* second measurement (ms)R2* second measurement (s–1)R2* has a constant standard error that makes assessment of the significance of changes easierWestwood M, et al. J Magn Reson Imaging. 2003;18:33-9.
27 MRI scanners Manufacturers Siemens Healthcare (Erlangen, Germany;GE Healthcare (Milwaukee, WI, USA;Philips Healthcare (Best, the Netherlands;Magnetic fieldT2* varies with magnetic field strength1need 1.5 T for cutoff levels of 20 ms (iron overload) and 10 ms (severe iron overload)1,2Cardiac packageneeds to be acquired separately from the manufacturers. The cost is about USD 40,000. However, in most centres, this is available since MRI is frequently used in non-iron-related cardiovascular imagingincludes all necessary for acquisition of the imagesequences are included in Siemens and Philips Healthcare cardiac packages, but for GE Healthcare they need to be acquired separately (note: variations may exist between countries)1Anderson LJ, et al. Eur Heart J. 2001;22: Kirk P, et al. Circulation. 2009;120:
28 Cardiac T2* MRI in practice: The process 3. Analysis of MRI data (time depends on experience*)1. Patient preparation (5 min)2. Acquisition of the MRI image(approx min)Doctor with patient at the MRI scanner, Stock photo, File #:Man in Scanner, Stock photo , File #:T2*, R2**Time to manually calculate T2*/R2* values in an Excel spreadsheet depends on the experience of the physician.
29 Cardiac T2* MRI in practice: The process (cont.) Preparation of the patientAcquisition of the imageAnalysis of the data (post-processing)Excel spreadsheetThalassaemiaTools, CMRtoolscmr42FerriScanMRmapMATLAB
31 Preparation of the patient Standard precautions need to be takenThere is no need for peripheral vein access since no contrast agent is requiredSpecial careremove all infusion/medication pumps (e.g. with insulin, pain-relieving drugs)stop continuous i.v. application of ICT during the measurementECG signal should be positioned according to scanner specificationsECG = electrocardiography.
32 Cardiac T2* MRI in practice: The process (cont.) Preparation of the patientAcquisition of the imageAnalysis of the data (post-processing)Excel spreadsheetThalassaemiaTools, CMRtoolscmr42FerriScanMRmapMATLAB
34 Acquisition of the image: MRI pulse sequences are a preselected set of defined radio-frequency and gradient pulsesare computer programs that control all hardware aspects of the scandetermine the order, spacing, and type of radio-frequency pulses that produce magnetic resonance images according to changes in the gradients of the magnetic fieldSeveral different pulse sequences exist1a gradient-echo sequence generates T2*1Wood JC, Ghugre N. Hemoglobin. 2008;32:85-96.
35 The most common commercially available T2* acquisition techniques SequenceGroupNumber of echoes per breath-holdHeart regionsPre-pulseRR intervalsTRBright blood(Anderson et al.)1London (Pennell)1 (but multiple breath-holds)1 (septum)No1VariableNovel bright blood(Westwood et al)2MultipleFixedBlack blood(He et al)3-4Yes2Multi-slice(Pepe et al)5Pisa (Pepe)Multi-regionThe various techniques give clinically comparable results.2-3, 51Anderson LJ, et al. Eur Heart J. 2001;22: Westwood M, et al. J Magn Reson Imaging. 2003;18: He T, et al. J Magn Reson Imaging. 2007;25: He T, et al. Magn Reson Med. 2008;60: Pepe A, et al. J Magn Reson Imaging. 2006;23:662-8.
36 Acquisition of the image: TEs Images are taken at a minimum of 5 different TEs, normally 8‒121The choice of minimum TE determines the smallest measurable T21ideally, min TE 2 ms, max TE 17‒20 msDifferent T2* acquisition techniques according to TEmultiple breath-hold: acquire an image for each TE in separate breath-holds2single breath-hold multi-echo acquisition: acquire images for all TE during 1 breath-hold3Mean R2* compared with true value in the case of synthetic images for different minimum TEs, but same echo duration (18 ms)450045040035030025020015010050True R2* (Hz)Mean R2*: ramp, dualtone, & uniform (Hz)Shortest TE = 2 msShortest TE = 1 msShortest TE = 4 msShortest TE = 5.5 msTrue1Wood JC, Noetzli L. Ann N Y Acad Sci. 2010;1202: Anderson LJ, et al. Eur Heart J. 2001;22: Westwood M, et al. J Magn Reson Imaging. 2003;18: Ghugre NR, et al. J Magn Reson Imaging. 2006;23:9-16.
37 How does the MRI data output looks like? Data visualizationFrameTE (ms)Mean ST1.989.513.683.625.376.837.070.648.764.5510.459.2612.254.9713.950.2815.645.8917.342.4During a single breath hold the pulse sequence run several times at increasing echo time (TE), generating data points corresponding to decreased signal intensity11Wood JC, Ghugre N. Hemoglobin. 2008;32:85-96.
38 FAQ: Acquisition technique Which is recommended: single or multiple breath-hold technique?Comparison of the 2 methods, single and multiple breath-hold, showed no significant skewing between T2* values in all patients with -thalassaemia major, regardless of their T2* value (see Bland-Altman plots)1However, in cardiac MRI the most recommended technique is single breath-hold, because it allows quick acquisition of the information. This is especially important to avoid movement artefacts (heart beating, breathing) and assure the good quality of the MRI imagePatients with T2* < 20 ms1Patients with T2* 20 ms 11Westwood M, et al. J Magn Reson Imaging. 2003;18:33-9.
39 Acquisition of the image Single breath-hold multi-echo acquisitiontake a short-axis slice of the ventricle (halfway between the base and the apex): orange lineimage acquisition should occur immediately after the R wavedo not alter any settings that could alter TE (e.g. FOV)Image courtesy of Dr J. de Lara Fernandes.
40 Cardiac T2* MRI in practice: The process (cont.) Preparation of the patientAcquisition of the imageAnalysis of the data (post-processing)Excel spreadsheetThalassaemiaTools, CMRtoolscmr42FerriScanMRmapMATLAB
42 How T2* is calculated from the MRI output? Data visualizationCurve FittingT2*Noise levelT2* calculation is fitting a curve on the data points and calculating at what echo time no signal is left from iron (only noise)11Wood JC, Ghugre N. Hemoglobin. 2008;32:85-96.
43 Analysis of the dataThe data can be analysed manually or using post-processing softwareManuallyPost-processing softwareExcel spreadsheetThalassaemiaTools (CMRtools)cmr42FerriScanMRmapMATLAB
44 Analysis of the data (cont.) MethodProsConsExcel spreadsheetLow costTime-consumingTediousThalassaemiaTools (CMRtools)1Fast (1 min)2Easy to useFDA approvedGBP 3,000 per yearcmr42(3)FDA approved3Can generate T2*/R2* and T2/R2 maps with same softwareAllows different forms of analysisGenerates pixel-wise fitting with colour maps40,000 USD first year costs12,000 USD per year afterFDA = Food and Drug Administration.1www.cmrtools.com/cmrweb/ThalassaemiaToolsIntroduction.htm. Accessed Dec Pennell DJ. JACC Cardiovasc Imaging. 2008;1: www.circlecvi.com. Accessed Dec 2010.
45 Analysis of the data (cont.) MethodProsConsFerriScan1Centralized analysis of locally acquired data (206 active sites across 25 countries)Easy set-up on most MRI machinesEU approvedValidated on GE, Philips, and Siemens scannersUSD 100 per scanPatients data are sent to reference centreMRmap2Uses IDL runtime, which is a commercial software (less expensive than cmr42/CMRtools)Can quantify T1 and T2 map with the same softwarePurely a research toolNot intended for diagnostic or clinical useMATLAB3Low costAvailable only locallyPhysicists or engineers need to write a MATLAB program for display and T2* measurement1www.resonancehealth.com/resonance/ferriscan. Accessed Dec www.cmr-berlin.org/forschung/ mrmapengl/index.html. Accessed Dec Wood JC, Noetzli L. Ann N Y Acad Sci. 2010;1202:173-9.
46 FAQ: Mistakes in analysing the data What are the most common mistakes in analysing the data that could lead to a wrong interpretation of the T2* value?Interpreting the data from cardiac MRI is usually quite straightforward; problems may arise when analysing data from patients with severe cardiac iron overload. In this case, the signal from heavily iron-loaded muscle will decay quickly and a single exponential decay curve does not fit the data well.1Models exist that can help to solve this issue (see next slide):the offset model (Prof Wood and colleagues)truncation of the data (Prof Pennell and colleagues)Both models should give comparable results; the differences should not be clinically relevantSignal decay curve from a patient with T2* ≈ 5 ms, showing that the data do not fit well21Wood JC, Noetzli L. Ann N Y Acad Sci. 2010;1202: Ghugre NR, et al. J Magn Reson Imaging. 2006;23:9-16.
47 FAQ: Mistakes in analysing the data (cont.) What is truncation?After the selection of the ROI, the signal decay can be fitted using different models. In the truncation model, the late points in the curve that form a plateau are subjectively discarded; the objective is to have a curve with an R2 > A new single exponential curve is made by fitting the remaining signals.1Generally, a truncation model should be used with the bright-blood technique to obtain more reproducible and more accurate T2* measurements1What is an offset model?The offset model consists of a single exponential with a constant offset. Using only the exponential model can underestimate the real T2* values (at quick signal loss at short TE, there is a plateau), while inclusion of the offset model into the fitting equation can improve this.2Generally, the offset model is recommended to be used with the black-blood technique1He T, et al. Magn Reson Med. 2008;60: Ghugre NR, et al. J Magn Reson Imaging. 2006;23:9-16.
48 FAQ: How to start measuring cardiac iron loading? How to start measuring cardiac iron loading in a hospital? What steps need to be taken?To start assessing cardiac iron loading by MRI, these steps can be followed:Check MRI machine requirements1.5 TcalibratedBuy cardiac package from the manufacturer. It must include all that is necessary for acquisition of the data (the sequences are included with Siemens and Philips Healthcare cardiac packages, but for GE Healthcare they need to be acquired separately)Optional: buy software for analysing the data (if not, Excel spreadsheet can be used)Highly recommended: training of personnel for acquisition of cardiac MR images (e.g. functional analyses)Highly recommended: training of personnel on how to analyse the data with the chosen software
49 Implementation of liver and cardiac MRI 1.5T MRI ScannerUS$Yes½ day trainingLiverAnalysisExperienced radiologistNo1 day trainingPost-processing analysisUS$ or US$4.000/yor in-house or outsourceCardiac acquisition packageUS$50.000Yes1-2 day trainingHeartAnalysisRoutine cardiac MR examsNo4 day trainingSlide presented at Global Iron Summit With the permission of Juliano de Lara Fernandes
51 SummaryIron overload is common in patients who require intermittent or regular blood transfusions to treat anaemia and associated conditionsAnalysing cardiac iron levels is importantin β-thalassaemia major, cardiac failure and arrhythmia are risk factors for mortalityin MDS, cardiac iron overload can have serious clinical consequencesdue to improved monitoring and management of iron overload over the last decade, 77% of patients have normal cardiac T2*1MRI: the method to rapidly and effectively assess cardiac iron loadingT2* allows specific assessment of cardiac iron levels. The use of this convenient, non-invasive procedure has had a significant impact on outcomes in patients with cardiac iron overload1R2* is a simple calculation from T2* and has a linear relationship with cardiac iron concentration1Thomas AS, et al. Blood. 2010;116:[abstract 1011]. 2Modell B, et al. J Cardiovasc Magn Reson. 2008;10:42-9.
56 GLOSSARY LIC = liver iron concentration LVEF = left-ventricular ejection fractionMCA = middle cerebral arteryMDS = Myelodysplastic syndromesMDS-U = myelodysplastic syndrome, unclassifiedMRA = magnetic resonance angiographyMRI = magnetic resonance imagingMV = mean velocity.N = neutropeniaNEX = number of excitationsNIH = National Institute of HealthOS = overall survival
57 GLOSSARY pB = peripheral blood PI = pulsatility index PSV = peak systolic VelocityRA =refractory anemiaRAEB = refractory anemia with excess blastsRAEB -T = refractory anemia with excess blasts in transformationRARS = refractory anemia with ringed sideroblastsRBC = red blood cellsRF = radio-frequencyRCMD = refractory cytopenia with multilineage dysplasiaRCMD-RS = refractory cytopenia with multilineage dysplasia with ringed sideroblastsRCUD = refractory cytopenia with unilineage dysplasia
58 GLOSSARY RN = refractory neutropenia ROI = region of interest RT = refractory thrombocytopeniaSCD = sickle cell diseaseSD = standard deviationSI = signal intensitySIR = signal intensity ratioSF = serum ferritinSNP-a = single-nucleotide polymorphismSQUID = superconducting quantum interface device.STOP = = Stroke Prevention Trial in Sickle Cell AnemiaSTOP II = Optimizing Primary Stroke Prevention in Sickle Cell Anemia
59 GLOSSARY T = thrombocytopenia TAMMV = time-averaged mean of the maximum velocity.TCCS = transcranial colour-coded sonographyTCD = transcranial doppler ultrasonographyTCDI = duplex (imaging TCD)TE = echo timeTR = repetition timeWHO = World Health OrganizationWPSS = WHO classification-based Prognostic Scoring System