Using Ultrasound Elastography to Predict Development of Sinusoidal Obstruction Syndrome
Phase: NA
Conditions: Sinusoidal Obstruction Syndrome, Complications of Bone Marrow Transplant
Sponsor: Children's Mercy Hospital Kansas City

Ultrasound Elastography 
IRB # 15060244 
Page 1 of 9 
 
 
Using Ultrasound Elastography to Predict Development of Sinusoidal Obstruction 
Syndrome 
 
 
Principal Investigator: 
Sherwin Chan, MD PhD 
The Children’s Mercy Hospital 
Department of Radiology 
816-324-3273 
sschan@cmh.edu 
 
Co-Investigators: 
Erin Opfer, DO 
The Children’s Mercy Hospital 
Department of Radiology 
816-324-3273 
ekopfer@cmh.edu 
 
 
Biostatistics: 
Vincent Staggs, PhD 
The Children’s Mercy Hospital 
Health Services and Outcomes Research  
816-302-0165 
vstaggs@cmh.edu 
 
Research Personnel: 
Amie Robinson, BSRT(R)(MR), CCRP 
The Children’s Mercy Hospital 
Research Coordinator 
Department of Radiology 
816-302-8311 
alrobinson@cmh.edu 
 
Maura Sien 
The Children’s Mercy Hospital 
Research Coordinator 
Department of Radiology 
816-302-6065 
mesien@cmh.edu 
 
 
Study Site:  
Children's Mercy Hospital - Adele Hall Campus 
 
Protocol Version:  (6.0)                           
 
 
Protocol Date:  2-26-2020 
 
NCT #: NCT02483481 
 
 
 
 
 
 
 
 
 
 
 
 

Ultrasound Elastography 
IRB # 15060244 
Page 2 of 9 
 
1. STUDY OBJECTIVES/HYPOTHESIS 
Primary Objective 
Hepatic sinusoidal obstruction syndrome (SOS) or hepatic veno-occlusive disease (VOD) 
is a complication of hemopoetic stem-cell transplantation that results from injury to the 
venous endothelium causing hepatic venous outflow obstruction at the level of the 
venules and sinusoids.  Other causes of SOS include liver transplant, radiation therapy, 
chemotherapy and alkaloid ingestion.  Clinically, it is characterized by hepatomegaly, 
jaundice, right upper quadrant pain and ascites.  Traditional ultrasound imaging criteria 
for the diagnosis of SOS have been shown to have poor sensitivity and specificity.  Our 
hypothesis is that quantitative shear wave ultrasound elastography will be more accurate 
in detecting this disease compared with conventional ultrasound parameters. 
Secondary Objective 
Our secondary hypothesis is that to quantitative shear wave ultrasound elastography will 
be more accurate in determining that SOS/VOD is severe ( See Table 2 for grading) 
compared with conventional ultrasound parameters.  
2.   BACKGROUND 
 
Sinusoidal obstruction syndrome (SOS) is a potentially fatal hepatic veno-occlusive 
disease-affecting children following bone marrow transplantation (BMT). SOS most 
likely develops secondary to sinusoidal endothelial damage and subsequent obstruction. 
The disease can be separated into mild, moderate, and severe forms; almost all patients 
diagnosed with severe SOS will die from this disease 1. Children with severe SOS suffer 
from multi-organ failure with signs and symptoms of portal hypertension (ascites, 
varices, edema), renal and respiratory failure 1,2. Although these children may be few and 
far between, the mere severity of the disease process and awful prognosis factors are 
valid reasons for more medical attention. SOS is usually diagnosed via clinical criteria 
and, despite available prophylaxis and treatment, children continue to die from this 
devastating disease. There have been a few retrospective and prospective studies 
examining ultrasound in adults BMT patients, which have showed limited effectiveness 
of traditional ultrasound parameters to detect SOS 3-7. 
 
Quantitative shear wave ultrasound elastography with acoustic force radiation imaging is 
an emerging technology that uses ultrasound pressure waves to provide an estimate of 
tissue stiffness8-11. This technique is promising for pediatric imaging because it is 
portable, quick to perform, relatively low cost and involves no ionizing radiation.  
Acoustic force radiation imaging and ultrasound elastography does not have any 
increased risks over conventional ultrasound imaging8-13. It has been studied in pediatric 
liver imaging14-16, placental imaging13, thyroid imaging17,18 and musculoskeletal 
imaging19. 
 
Table 1. A table to show the clinical criteria for veno-occlusive disease 
 
 Modified Seattle Criteria  
 
Baltimore Criteria  
 

Ultrasound Elastography 
IRB # 15060244 
Page 3 of 9 
 
Two of the following criteria must be 
present with in 20 days of SCT 
 
Bilirubin must be >  2mg/dL before 21 
days SCT and two of the following criteria 
must be present 
Bilirubin > 2mg/dL 
 
 Ascites ( Physical exam or radiographic) 
Hepatomegaly increased over baseline 
 
Weight gain > 5 %above baseline weight 
* 
Ascites ( Physical exam or radiographic) 
and /or Weight gain > 5 %above baseline 
weight  
 
Hepatomegaly increased over baseline 
 
 
Table 2.   Staging of VOD/SOS 20 
Mild :  Resolved without interventions  
Moderate : Requires treatment  
• Bilirubin > 6 mg/dl  
• AST > 5 times upper limit of normal  
• Weight gain > 5 %  
• Ascites  
Severe : Progression to Multi-organ dysfunction syndrome  
• Respiratory failure ( O2 saturation < 90 %) 
• Hepato renal syndrome  
• Encephalopathy  
• Severe renal failure ( creatinine > x 2) 
• Bilirubin > 20 mg/ dl  
 
3. RATIONALE 
SOS is a disease with a low incidence but high mortality rate once diagnosed.  There are 
treatments available for this disease if diagnosed early.  Currently, no good imaging 
prognostic factors are known.  Some imaging criteria for SOS are available but all detect 
the disease after it has been clinically confirmed. 
If we can discover an imaging modality that can more accurately diagnose SOS and 
determine prognosis at the time of imaging, then we can guide how aggressive to be with 
the available interventions that can slow progression or stop the disease. 
4. STUDY DESIGN 
 

Ultrasound Elastography 
IRB # 15060244 
Page 4 of 9 
 
This is a single site prospective cohort study that will compare ultrasound elastography to 
traditional ultrasound parameters in bone marrow transplant patients who are at risk for 
development of SOS. 
5. TARGET STUDY POPLUATION SPECIFICS 
Inclusion Criteria 
 
All patients Age < 21 years who are undergoing allogenic or autologous 
myeloablative stem cell transplant. 
Exclusion Criteria 
• Any patient who is undergoing reduced intensity conditioning regimen for stem 
cell transplant. 
• Any other medical or social condition that in the opinion of the investigator would 
make them unsuitable to participate.   
6. DATA COLLECTION 
Data Collection Procedures 
• Candidates for the study will be identified by the Hematology Oncology service 
when they are admitted for bone marrow transplant. 
 
• A member of the study team will consent that patient and/or their parents once the 
patient has been identified. 
 
• If the patient consents to the study, three limited abdominal Doppler ultrasound 
(US) and shear wave elastography will be performed. The initial US and 
elastography will be performed within a week from receiving condition regimen, 
second US and elastography on Day +3 to Day + 7 of transplant (preferably on 
day + 5 of transplant) and lastly, on Day +12 to Day +16 (preferably on Day +14) 
 
• Demographic, laboratory and clinical variables will be collected from CIBMTR 
research registry database (IRB# 11120281) as well as from the EMR from the 
time of initial ultrasound and through day 100 post-transplant.  
For subjects whom consented to take part in the CIBMTR database, a data 
request from CIBMTR will be requested using the assigned CRID number 
for each subject. 
Subjects that did not consent for CIBMTR database will have 
demographic, laboratory and clinical variables collected out of EMR into 
REDCap. 
Data will provided from CIBMTR in the form of a spreadsheet and will be 
password protected and sent to CMH only for data analysis. 

Ultrasound Elastography 
IRB # 15060244 
Page 5 of 9 
 
Clinical and outcome data, including DOB, dates of service, exams, lab 
values and clinical timepoints will be evaluated. 
 
• Multiple shear wave elastography measurements of the liver will be obtained 
during any post-transplant clinical abdominal ultrasounds. 
 
Table 3. Timeline for obtaining the limited abdominal Ultrasound and 
Elastography 
First Ultrasound Exam  
Within a week prior to receiving 
conditioning regimen  
Second Ultrasound Exam 
Day +4 to Day + 7 of transplant 
(Preferably on day + 5 of transplant) 
Third Ultrasound Exam 
Day +12 to Day +16 of transplant 
(Preferable on Day +14 of transplant) 
Further Ultrasound Exam 
Performed based on clinical necessity.  
Elastography will be performed with 
every ultrasound.  
Records to be kept 
Protected health information (PHI) to be collected for the purpose of this study alone 
will include; age, gender, race, MRN, date of transplant, dates of ultrasound exams. 
This information will be documented in RedCap and CIBMTR password protected 
spreadsheet.  Within RedCap, there will be two separate files.  One file will exclude 
PHI and contain study data according to an assigned study ID number.  The second 
file, will contain a master list of subjects linking the subject PHI with the assigned 
study ID #.  The research record generated will consist of an excel spreadsheet from 
the data dictionary within RedCap. Security measures include: storage of the data on 
a password protected computer in a restricted assess departmental folder limited to 
only identified study personnel. 
Secure Storage of Data 
CIBMTR data will be stored on the hospital server and REDCap data will be 
manually entered and stored on the hospital server.  Development of data entry record 
will occur in collaboration with Medical Information Technology to ensure 
compliance and completeness.  The Children’s Mercy Hospital (CMH) Windows-
based network is configured with the security of an individualized log in on a server 
that is backed up daily.  Resources provide full support for electronic data collection, 
storage, analysis and exchange.  The network is maintained by the Hospital 
Information Services professional staff.  CMH has two firewall protected Internet 
connections that allow transmission of large data and graphics files between CMH 
investigators and collaborators with I-2 connections.  CMH has secure transport 
appliances that use SSH, SFTP, and FTPS protocols to allow researchers to transmit 
and receive large datasets manually or automatically.     
 

Ultrasound Elastography 
IRB # 15060244 
Page 6 of 9 
 
Study data points will be entered into the RedCap research record, according to 
assigned study ID#.   A master list linking only subject medical record number with 
assigned study number will be maintained in a separate, RedCap data file.  
7. STUDY DURATION/STUDY TIMELINE 
 
Stage 1, patient accrual and data collection (2015-2017) 
Stage 2, data analysis (2017-2018) 
Stage 3, presentation and publication (2018) 
Projected start date:  Novemeber 1, 2015 
Total length of time: two years  
Approximate end date of the study:  June 1, 2018 
8. STATISTICAL CONSIDERATIONS 
Measures 
• Primary measure: presence or absence of SOS (clinical determination from 
provider, will refer to Cerner chart) 
• Secondary measure: severity of SOS (Cerner chart) 
  
General Design Issues 
• Primary objective: compare sensitivity and specificity of traditional ultrasound 
parameters and ultrasound elastography of the liver for detecting SOS in BMT 
patients. 
•  Secondary objectives: 1. compare sensitivity and specificity of traditional 
ultrasound parameters and ultrasound elastography of the liver for identifying 
severe SOS in BMT patients.   
 
Sample size determination 
 
Previous articles showed that patients with SOS had velocities of 2.75 and 2.58 m/s 
versus velocities of 1.08 m/s in normal controls20,21. The incidence of SOS in our BMT 
patient is estimated to be around 10% and about 40 patients undergo transplant here in 1 
year.  So assuming a two year interval, we would have 8 patients with BMT and SOS and 
72 patients with BMT and no SOS.  Based on a mean velocity of 2.66 m/s in SOS 
patients and 1.08 m/s in non-SOS patients and a standard deviation of 1 m/s in both 
populations, a two-sided t-test would have a power of 0.987 for detecting a statistically 
significant (p<0.05) difference between the means 
 
Data Analyses 
We will perform two-sided t-tests and nonparametric tests for categorical and continuous 
data, respectively. Additionally, we will perform a multivariate regression to determine 
which variables are significantly correlated to severe SOS (table 2) and calculate an odds 
ratio for each of these variables. If a patient is missing any imaging or clinical data, then 
this patient will be excluded from those parts of the data analysis, but the rest of their data 
will still be included in the study. 

Ultrasound Elastography 
IRB # 15060244 
Page 7 of 9 
 
HUMAN SUBJECTS  
Institutional Review Board (IRB) Review and Informed Consent 
Potential subjects will be identified by the Hematology/Oncology service once they are 
scheduled for BMT. Once potential subjects are identified and general eligibility is 
determined, a member of the study team will approach the patient and their family and 
present the study to them. If the parent(s)/legal guardian deny an interest in the study, 
they are thanked for their time and are not subsequently contacted again.  
Subject Confidentiality 
 
 Each subject’s medical record will be reviewed by research staff and data entered into 
the research record. A master linking list will be maintained in the REDCap database and 
this list will only be visible to study personnel. 
Study Modification/Discontinuation 
The study may be modified or discontinued at any time by the IRB,  the OHRP, the FDA 
or other Government agencies as part of their duties to ensure that research subjects are 
protected. 
9. PUBLICATION OF RESEARCH FINDINGS 
 
Results are intended to be presented at the Society of Pediatric Radiology 2017 annual 
meeting.  
Results are intended to be published in the radiology or hematology trade journals in 
2017. 
10. REFERENCES 
 
1. 
McDonald GB, Hinds MS, Fisher LD, et al. Veno-occlusive disease of the liver 
and multiorgan failure after bone marrow transplantation: a cohort study of 355 
patients. Ann Intern Med. 1993;118(4):255-267. 
2. 
Carreras E, Bertz H, Arcese W, et al. Incidence and outcome of hepatic veno-
occlusive disease after blood or marrow transplantation: a prospective cohort 
study of the European Group for Blood and Marrow Transplantation. European 
Group for Blood and Marrow Transplantation Chronic Leukemia Working Party. 
Blood. 1998;92(10):3599-3604. 
3. 
Hommeyer SC, Teefey SA, Jacobson AF, et al. Venocclusive disease of the liver: 
prospective study of US evaluation. Radiology. 1992;184(3):683-686. 
4. 
Teefey SA, Brink JA, Borson RA, Middleton WD. Diagnosis of venoocclusive 
disease of the liver after bone marrow transplantation: value of duplex 
sonography. AJR Am J Roentgenol. 1995;164(6):1397-1401. 
5. 
Garcia-Criado A, Gilabert R, Salmeron JM, et al. Significance of and contributing 
factors for a high resistive index on Doppler sonography of the hepatic artery 

Ultrasound Elastography 
IRB # 15060244 
Page 8 of 9 
 
immediately after surgery: prognostic implications for liver transplant recipients. 
AJR Am J Roentgenol. 2003;181(3):831-838. 
6. 
Nicolau C, Bru C, Carreras E, et al. Sonographic diagnosis and hemodynamic 
correlation in veno-occlusive disease of the liver. J Ultrasound Med. 
1993;12(8):437-440. 
7. 
Herbetko J, Grigg AP, Buckley AR, Phillips GL. Venoocclusive liver disease 
after bone marrow transplantation: findings at duplex sonography. AJR Am J 
Roentgenol. 1992;158(5):1001-1005. 
8. 
Bamber J, Cosgrove D, Dietrich CF, et al. EFSUMB guidelines and 
recommendations on the clinical use of ultrasound elastography. Part 1: Basic 
principles and technology. Ultraschall Med. 2013;34(2):169-184. 
9. 
Cosgrove D, Piscaglia F, Bamber J, et al. EFSUMB guidelines and 
recommendations on the clinical use of ultrasound elastography. Part 2: Clinical 
applications. Ultraschall Med. 2013;34(3):238-253. 
10. 
Shiina T, Nightingale KR, Palmeri ML, et al. WFUMB guidelines and 
recommendations for clinical use of ultrasound elastography: Part 1: basic 
principles and terminology. Ultrasound Med Biol. 2015;41(5):1126-1147. 
11. 
Stenzel M, Mentzel HJ. Ultrasound elastography and contrast-enhanced 
ultrasound in infants, children and adolescents. Eur J Radiol. 2014;83(9):1560-
1569. 
12. 
Ferraioli G, Filice C, Castera L, et al. WFUMB guidelines and recommendations 
for clinical use of ultrasound elastography: Part 3: liver. Ultrasound Med Biol. 
2015;41(5):1161-1179. 
13. 
Sugitani M, Fujita Y, Yumoto Y, et al. A new method for measurement of 
placental elasticity: acoustic radiation force impulse imaging. Placenta. 
2013;34(11):1009-1013. 
14. 
Kutty SS, Peng Q, Danford DA, et al. Increased hepatic stiffness as consequence 
of high hepatic afterload in the Fontan circulation: a vascular Doppler and 
elastography study. Hepatology. 2014;59(1):251-260. 
15. 
Leschied JR, Dillman JR, Bilhartz J, Heider A, Smith EA, Lopez MJ. Shear wave 
elastography helps differentiate biliary atresia from other neonatal/infantile liver 
diseases. Pediatr Radiol. 2015;45(3):366-375. 
16. 
Ozmen E, Adaletli I, Kayadibi Y, et al. The impact of share wave elastography in 
differentiation of hepatic hemangioma from malignant liver tumors in pediatric 
population. Eur J Radiol. 2014;83(9):1691-1697. 
17. 
Lin P, Chen M, Liu B, Wang S, Li X. Diagnostic performance of shear wave 
elastography in the identification of malignant thyroid nodules: a meta-analysis. 
European radiology. 2014;24(11):2729-2738. 
18. 
Liu B, Liang J, Zheng Y, et al. Two-dimensional shear wave elastography as 
promising diagnostic tool for predicting malignant thyroid nodules: a prospective 
single-centre experience. European radiology. 2015;25(3):624-634. 
19. 
Lacourpaille L, Hug F, Guevel A, et al. Non-invasive assessment of muscle 
stiffness in patients with Duchenne muscular dystrophy. Muscle Nerve. 
2015;51(2):284-286. 
20. 
Fontanilla T, Hernando CG, Claros JC, et al. Acoustic radiation force impulse 
elastography and contrast-enhanced sonography of sinusoidal obstructive 

Ultrasound Elastography 
IRB # 15060244 
Page 9 of 9 
 
syndrome (Veno-occlusive Disease): preliminary results. J Ultrasound Med. 
2011;30(11):1593-1598. 
21. 
Son CY, Kim SU, Han WK, et al. Normal liver elasticity values using acoustic 
radiation force impulse imaging: a prospective study in healthy living liver and 
kidney donors. J Gastroenterol Hepatol. 2012;27(1):130-136.