Validation of Baveno VII Criteria and Spleen Stiffness Measurement on Outcome Prediction in Patients With Hepatocellular Carcinoma
Conditions: HCC - Hepatocellular Carcinoma, Cirrhosis
Sponsor: Chinese University of Hong Kong

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Clinical Study Protocol 
Validation of Baveno VII criteria and spleen stiffness 
measurement on outcome prediction in patients with 
hepatocellular carcinoma 
Short title: BASS_HCC study 
 
Principal Investigator: 
 
Dr. Jimmy Che-To Lai, Resident Specialist, Department of Medicine and Therapeutics, Prince 
of Wales Hospital  
 
Co-investigators: 
 
 
Prof. Vincent Wai-Sun Wong, Professor, Department of Medicine and Therapeutics, The 
Chinese University of Hong Kong 
Prof. Grace Lai-Hung Wong, Professor, Department of Medicine and Therapeutics, The 
Chinese University of Hong Kong  
 
Prepared by:  
Dr. Jimmy Che-To Lai 
Protocol version:  
1.1 
Date:   
 
11 June 2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. BACKGROUND 
1.1 Significance of chronic liver disease and hepatocellular carcinoma  
Hepatocellular carcinoma (HCC) burdens the global healthcare system with a drastic increase 
in incidence by 70% from 1990 to approximately 747,000 cases and 480,000 deaths in 2019.(1)  
Despite implementation of screening ultrasound in at-risk populations and advances in the 
treatment of HCC in recent decades, HCC remains a lethal malignancy with a median survival 
of less than a year.(2-4) Apart from the oncological factors, the underlying liver disease has an 
important impact on morbidity and mortality in patients with HCC as most HCC develop under 
the setting of chronic hepatic inflammation and fibrosis from patients with advanced chronic 
liver diseases of various aetiologies.(5, 6) 
 
1.2 Non-invasive measurement of portal hypertension 
In the Baveno VI consensus, the term “compensated advanced chronic liver disease” (cACLD) 
described spectrum of chronic liver diseases ranging from advanced liver fibrosis to 
compensated cirrhosis.(7) Patients with cACLD are at risk of hepatic decompensation and 
development of HCC, especially for those with clinically significant portal hypertension 
(CSPH), which is conventionally measured invasively by hepatic venous pressure gradient 
(HVPG).(8) The recently updated Baveno VII consensus implemented a non-invasive 
approach by incorporating liver stiffness measurement (LSM) by vibration-controlled transient 
elastography (VCTE) and platelet count in ruling in or out CSPH in patients with cACLD.(9) 
In the Baveno VII consensus and as well incorporated into the latest practice guidance on portal 
hypertension, LSM ≤ 15kPa and platelet count ≥ 150 x 109/L rules out CSPH, whereas LSM > 
25kPa, LSM 20-25kPa with platelet count <150 x 109/L or LSM 15-20kPa with platelet count 
<110 x 109/L rule in CSPH, prompting the presence of gastroesophageal varices.(10) As well 
in Baveno VI consensus, LSM < 20 kPa with platelet count > 150 x 109/L also implies a 
minimal risk of high-risk varices and thus can have a screening oesophagogastroduodenoscopy 
(OGD) spared.(7) 
 
The development of spleen stiffness measurement (SSM) by VCTE also revolutionised the 
field by demonstrating its correlation with portal pressure and CSPH.(11) Studies have shown 
that, by combining Baveno VII criteria with SSM, the accuracy in identifying CSPH (such as 
the presence of high-risk varices) was enhanced compared to adopting Baveno VII criteria 
alone.(12-14) 

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1.3 Unmet need 1: Conflicting data on LSM/SSM in prediction of hepatic events 
in HCC patients 
Use of LSM and SSM in prediction of HCC recurrence was reported in a few previous studies. 
The studies involved a one-stop LSM and/or SSM measurements with longitudinal follow-up 
on the recurrence rate of HCC. For instance, high baseline LSM was shown to be a poor 
prognostic factor in patients with HCC receiving radiofrequency ablation, and achieving low 
LSM reduced HCC recurrence.(15, 16) Another prospective study involving 175 patients with 
HCC suitable for resection showed that SSM was the only predictor for late HCC 
recurrence.(17)  
 
However, there are lack of data in the prediction of hepatic decompensation in patients with 
HCC. First, studies aiming to investigation on risk prediction of decompensation either 
excluded patients with HCC or regarded HCC as one of the study endpoints. Second, the 
present data available also showed conflicting results. For instance, two retrospective studies 
performed from our group suggested that Baveno VII criteria (ie. LSM by VCTE and platelet 
count) could accurately identify high risk varices and hepatic events in both advanced HCC 
and that of different Barcelona Clinic Liver Cancer (BCLC) stages.(18, 19) On the contrary, 
another retrospective suggested that the use of both Baveno VI or VII criteria were inaccurate 
in predicting the presence of high-risk varices or CSPH measured by HVPG across different 
stages of HCC.(20) Heterogeneity was present in the study subjects and data analysis among 
different studies, leading to divergent results. SSM as well was not included in these studies 
and that the effect of combined Baveno VII and SSM in prediction of decompensation in HCC 
patients is still uncertain. 
 
1.4 Unmet need 2: Lack of standardisation and serial LSM/SSM measurement 
Serial liver stiffness monitoring was reported for longitudinal assessment and risk estimation 
of hepatic events in some chronic liver diseases, notably metabolic-dysfunction associated 
steatotic liver disease.(21) Whether serial monitoring of LSM and SSM would have any clinical 
significance and prognostication on hepatic events or even HCC recurrence is not well 
ascertained. This is of high clinical relevance especially patients with HCC may undergo liver 
resection or other oncological treatments that possibly affect the residual liver volume and 
function.  

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Furthermore, studies are lacking in using spleen-dedicated module (SSM@100Hz) in 
measuring SSM in patients with HCC, as prior study used the liver-dedicated module 
(LSM@50Hz) to measure both LSM and SSM.(17) This may undermine the accuracy of the 
SSM results as the spleen is stiffness than the liver and the use of the LSM@50Hz module may 
potentially overestimate the SSM.(22) As SSM@100Hz has been shown to be a reliable and 
highly reproducible tool in assessing SSM,(23) there is an important need to confirm its 
validation in patients with HCC. 
 
2. STUDY OBJECTIVES 
1. We aim to test the hypothesis that serial monitoring of LSM and platelet count (ie. Baveno 
VII criteria), and SSM predicts hepatic events (including high-risk varices) in compensated 
patients with HCC for curative-intent treatment. 
2. We aim to assess the change in Baveno VII criteria and SSM in prediction of HCC 
recurrence in compensated patients after curative-intent treatment for HCC. 
3. We aim to validate the use 50Hz and 100Hz SSM module of VCTE in patients with 
compensated liver disease and HCC. 
4. We aim to identify factors associated with hepatic events (including high-risk varices), 
HCC recurrence and mortality, with a special focus on serial LSM and SSM obtained by 
VCTE. 
 
3. STUDY DESIGN OVERVIEW (Figure 1) 
This study is a single-centre, prospective cohort study. Consecutive patients with compensated 
liver disease and HCC for curative-intent treatment will be invited to this study. The study 
follow-up duration will be five years. The study consists of two parts. 
 
Part 1:  We will perform VCTE with LSM and SSM and check platelet count during pre-
operative assessment for patients with HCC for curative-intent treatment. At the same day, we 
will also perform OGD as screening for gastroesophageal varices. This part aims to establish 
the validity of using Baveno VII criteria and/or combined Baveno VII criteria and SSM in 
predicting high risk varices for patients with HCC. 
 

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Part 2: We will serially perform VCTE and checking platelet count at month 6 and then half-
yearly after the HCC is treated. Follow-up OGD will also be performed at month 12, month 36 
and month 60 post-operation, as well as if CSPH is first suggested according to the Baveno VII 
criteria. This part aims to establish Baveno VII criteria and/or combined Baveno VII criteria 
and SSM in predicting high-risk varices, hepatic decompensation, mortality and HCC 
recurrence, as well as to identify any factors associated with these events. 
 
4. PATIENTS 
Consecutive patients with HCC coming into the surgical ambulatory care centre, hepatobiliary 
surgical clinics, joint hepatoma clinic as well as hepatology clinics for pre-operative 
assessment in Prince of Wales Hospital in Hong Kong will be screened for the following 
eligibility criteria:  
 
4.1 Inclusion criteria 
• Aged 18 or above 
• Known chronic liver disease(s) 
• HCC for curative-intent treatment (defined by HCC diagnosed with typical radiological 
features or histology, and planned for surgical resection or local ablative therapy as a 
curative-intent treatment) 
 
4.2 Exclusion criteria 
• Current or history of decompensated liver cirrhosis (i.e. Child’s C cirrhosis, prior 
decompensating events such as ascites, variceal bleeding, hepatic encephalopathy and 
hepatorenal syndrome) 
o Child’s B cirrhosis without decompensating events is not excluded 
• Past history of HCC (ie. The current HCC is a recurrence of priorly treated HCC or a 
second de novo HCC after previous first HCC) 
• Non-primary liver tumour (such as secondary liver tumour due to metastasis from 
another distant primary tumour) 
• History of liver transplantation or plan for liver transplantation as the modality of 
curative-intent HCC treatment 
• Asplenism or history of splenectomy 
• Contraindication to OGD (eg. Intestinal perforation of obstruction) 

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• Serious medical illness with limited life expectancy of less than 6 months 
• Pregnancy 
• Unable to obtain or refusal of informed consent from patient 
 
5. CLINIC VISITS AND ASSESSMENTS 
5.1 Clinical assessments 
The following procedures will be performed at baseline and half-yearly post-HCC treatment 
until month 60: 
• Documentation of medical history and new symptoms 
• Documentation of details of HCC (number, size and location) 
• Documentation of the presence of portal vein thrombosis 
• Documentation of high-risk varices, hepatic events and their dates of occurrence (i.e., 
ascites, 
spontaneous 
bacterial 
peritonitis, 
variceal 
haemorrhage, 
hepatic 
encephalopathy, hepatorenal syndrome-acute kidney injury, HCC, liver transplantation) 
• Dates and causes of death for patients who pass away between visits will be recorded 
• Physical examination 
• Anthropometric measurements including body weight, height, waist and hip 
circumferences, will be collected. Body mass index will be calculated as body weight 
(kg) divided by height (m) squared 
• Blood pressure and pulse rate measured after a 15-minute rest  
• Blood tests will include complete blood count, prothrombin time, renal function test, 
liver blood test (including alanine aminotransferase, aspartate aminotransferase and 
gamma-glutamyl transpeptidase), and alpha-fetoprotein 
• Store 10 mL of clotted blood and 10 mL of EDTA blood for future genetic and 
biochemical research 
 
5.2 Vibration-controlled transient elastography (VCTE) 
LSM and SSM assessments will be carried out using VCTE (FibroScan 630 Expert, Echosens, 
Paris, France). Operators with a minimum of 500 examinations completed and trained 
according to the manufacturer’s guidelines will conduct the tests.(24) Examinations will be 
performed at baseline, post-HCC treatment month 6 and then half-yearly till month 60. Ten 
measurements will be recorded each for the liver and spleen, and their median value will be 
used to derive the corresponding stiffness. The machine’s automated probe selection tool will 

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determine the use of M and XL probes for LSM, while SSM will be measured by both the M 
or XL probes (50Hz@LSM) as well as the dedicated 100Hz probe. 
 
LSM is considered reliable if there are ten or more valid measurements, and the interquartile 
range-to-median ratio of the measurements is ≤0.3. While no standardised reliability criteria 
exist for SSM, variability of SSM will be tracked in this study. 
 
5.3 Oesophagogastroduodenoscopy (OGD) 
OGD will be performed by experienced endoscopists with a minimum of 100 prior 
examinations, at baseline and post-HCC treatment month 12, month 36 and month 60, as well 
as if CSPH is first suggested according to the Baveno VII criteria.  
 
The scope of the examination will include the oesophagus, stomach, and the first and second 
parts of the duodenum. The size of varices will be graded using the modified Paquet 
classification (grade I for varices extending just above the mucosal level; grade II for varices 
projecting by one-third of the luminal diameter and non-compressible upon air insufflation; 
and grade III for varices projecting up to 50% of the luminal diameter and in contact with each 
other).(25) Additionally, the location and presence of red wale markings will be documented. 
Those with high-risk varices, defined by varices of grade II or above, or the presence of red 
wale markings, will be treated by non-selective beta-blocker with carvedilol and/or endoscopic 
variceal ligation, as per latest international guideline suggestion.(10) 
 
5.4 Follow-up 
Other follow-up procedures will be considered as part of the standard of care and will be 
covered by local resources. These include but are unlimited to the treatment of chronic liver 
disease and co-morbid conditions as well as surveillance for recurrence of HCC through 
periodic imaging and/or alpha-fetoprotein testing. Patients will be scheduled for at least one 
annual visit or more frequently, as clinically indicated. At each visit, incident hepatic events 
and any HCC recurrence will be documented. 
 
6. DATA PROCESSING AND ANALYSIS 
6.1 Analysis datasets 

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Part 1: This analysis will include all eligible patients who meet the inclusion and exclusion 
criteria, and undergo VCTE and endoscopy at baseline.  
Part 2: The analysis will include all patients who receive serial VCTE and OGD per study 
timeline.  
 
6.2 Primary endpoint 
The primary endpoint of this study is the composite of incident high-risk varices, hepatic 
decompensation and liver-related mortality. Hepatic decompensation is defined by the 
presence of ascites, variceal bleeding, overt hepatic encephalopathy or hepatorenal syndrome. 
Ascites is defined by compatible clinical signs and confirmed with ultrasound or paracentesis. 
Intraperitoneal fluid detected only by ultrasound is not considered an endpoint. Variceal 
bleeding will be suspected if patients are presented with haematemesis or melaena or a decrease 
in the haemoglobin level of at least 2 g/dL. The diagnosis is made when OGD shows one of 
the following features: active bleeding from a varix, a “white nipple” overlying a varix, clots 
overlying a varix, or varices with no other potential source of bleeding.(10) Overt hepatic 
encephalopathy is evidenced if there is symptom or sign compatible with West Haven criteria 
grade II or above.(26) Hepatorenal syndrome is diagnosed if there is an increase in serum 
creatinine ≥0.3 mg/dL within 48 hours or ≥50% increase in serum creatinine that is known or 
presumed to have occurred within the preceding seven days, after excluding hypovolemia, 
shock, nephrotoxic agents and structural kidney damage.(27) 
 
6.3 Secondary endpoints 
Secondary endpoints include: 
• Development of each hepatic decompensation event 
• Recurrence of HCC 
• Change in hepatic function in terms of Child-Pugh and model for end-stage liver disease 
(MELD) scores 
• Change in LSM and SSM 
 
6.4 Sample size calculation 
From our retrospective study from 673 patients with HCC of different BCLC stages recruited 
from 2013 to 2019 in Prince of Wales Hospital, 67.3% (453/673) were BCLC stage 0 and A 
(69 in stage 0 and 384 in stage A). The baseline LSM was 9.5-9.6kPa in these two BCLC stages. 

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At a median follow-up duration of 45.8 months, 127 (28.0%) of those in BCLC stage 0 (18.8%) 
and A (29.7%) developed hepatic events or liver-related mortality.(18) From another 
retrospective study on 533 patients with metabolic-dysfunction associated steatotic liver 
disease, 19.5% had worsening of LSM >20% from baseline, and change in LSM was the 
independent factor associated with hepatic decompensation (hazard ratio [HR] 1.56, p=0.04) 
and liver-related mortality (HR 1.96, p=0.02).(28) It is rational to believe that the HR is higher 
in patients with HCC with the use of composite primary endpoints. Also, the event rate will be 
higher in our study as incident high-risk varices are part of the composite primary endpoint. 
Using the Fine-Gray subdistribution regression model, assuming 30% of patients with HCC 
undergoing curative-intent treatment will have LSM/SSM deterioration leading to the 
development of the composite endpoint of high-risk varices, hepatic decompensation and liver-
related mortality at a rate of 35% at 5 years, 127 patients are required to provide 80% power to 
detect a minimum subdistribution HR of 2.5 with 2-sided 95% confidence interval. Assuming 
up to 20% dropout rate, a total of 159 patients will be required in this study. 
 
6.5 Data analysis 
Continuous variables were expressed in mean ± standard deviation or median (interquartile 
range [IQR]), as appropriate, while categorical variables were presented as number 
(percentage). Qualitative and quantitative differences between subgroups were analysed by 
chi-square or Fisher’s exact tests for categorical parameters and Student’s t test or Mann-
Whitney test for continuous parameters, as appropriate. Qualitative and quantitative differences 
between ordinal subgroups were analysed by chi-squared test for linear trend or Fisher’s exact 
tests for categorical parameters and one-way ANOVA or Kruskal-Wallis test for continuous 
parameters, as appropriate. Patients were followed until the occurrence of the endpoint, and 
censored upon the time of liver transplantation or at the end of follow-up period, whichever 
occurs earlier. Patients who withdraw consent will be censored assuming no endpoints 
developed after the last documented clinic visit. The primary and secondary endpoints will be 
analysed as time-to-event variables with hazard ratio and 95% confidence interval (CI) 
calculated. Event rates of endpoints will be compared with stratified log-rank test. Survival 
will be estimated by Kaplan-Meier method. Non-liver related mortality is considered a 
competing risk for the primary endpoint. 
 

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The accuracy of Baveno VII and/or SSM models in predicting high-risk varices and hepatic 
decompensation will be evaluated using the area under the receiver-operating characteristic 
curve with corresponding 95% CI. The corresponding sensitivity, specificity, positive 
predictive value and negative predictive value will be calculated. Multivariable logistic 
regression model will be performed to identify independent factors associated with hepatic 
decompensation and recurrence of HCC. All statistical tests are two-sided with p-value <0.05 
indicating statistical significance. As patients may be started on NSBB or receive endoscopic 
variceal ligation during the study, a subgroup analysis will be performed for those who do not 
receive these treatments. Use of NSBB and prior endoscopic variceal ligation are also included 
as covariates in the multivariable analysis. 
 
We hypothesise that non-invasive tests could detect hepatic decompensation, CSPH and 
recurrence of HCC at earlier timepoints. Therefore, we will examine baseline and follow-up 
LSM, SSM, platelet count, and their combinations, together with baseline demographics, liver 
biochemistry and baseline characteristics of HCC as potential predictors of these endpoints. 
 
6.6 Anticipated challenges and contingency plans 
Our team possesses the expertise and track records required to execute this study successfully. 
In case of challenges in recruitment, we have plans to invite other local centres for case referral 
as well as to include collaborating sites. Currently, our university is leading a multicentre 
randomised controlled trial on the use of carvedilol in treating patients with CSPH with 
participating sites in Malaysia and France. There is potential to expand the proposed project 
and accelerate enrolment. 
 
Endoscopy is an invasive procedure. Based on our previous clinical trials , a small percentage 
(typically <5%) of patients may decline the follow-up endoscopy. These patients will still be 
included in the analysis as described above, ensuring that their data continues to contribute to 
the study’s findings. 
 
7. ETHICS 
7.1 Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favourable opinion in writing by our Joint CUHK-NTEC CREC. The 

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protocol must be re-approved by our Joint CUHK-NTEC CREC annually. All subsequent 
protocol amendments must be approved by the CREC. 
 
7.2 Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements 
and our Joint CUHK-NTEC CREC. This study is designed based on a thorough knowledge of 
the scientific background, a careful assessment of risks and benefits, have a reasonable 
likelihood of benefit to the population studied and will be conducted by suitably trained 
investigators using approved protocol. 
 
7.3 Written informed consent 
The investigator(s) will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study. The informed 
consent forms are available in both English and Chinese. Subjects must also be notified that 
they are free to discontinue from the study at any time. The subject should be given the 
opportunity to ask questions and allow time to consider the information provided. The subject’s 
signed and dated informed consent must be obtained before conducting any procedure specific 
for the study. The Principal Investigator must store the original, signed Informed Consent Form. 
One copy of the signed Informed Consent Form must be given to the subject. If modifications 
are made according to local requirements, the new version has to be approved by our Joint 
CUHK-NTEC CREC. 
 
7.4 Data sharing 
In line with current international standard of accountability and transparent reporting, data from 
this study may be shared with outside parties upon reasonable request. Care will be taken to 
remove sensitive data (name, identity numbers and dates of birth) before data sharing. 
 
8. POSSIBLE RISKS AND ADVERSE EVENT REPORTING 
8.1 Possible risks and discomfort 
There is minimal discomfort in blood taking and undergoing VCTE. Major complications of 
OGD include bleeding and perforation but the major complication rate is overall less than 0.1%. 

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The adverse event reporting period for this study is from signing the informed consent through 
30 days after the last follow-up visit. 
 
8.2 Adverse event 
An adverse event is any undesirable medical event occurring in the subject within the trial 
period, whether or not it is related to the study intervention. 
 
The severity of an adverse event is defined as: 
Mild: Transient symptoms, no interference with the subject’s daily activities 
Moderate: Marked symptoms, moderate interference with the subject’s daily activities 
Severe: Severe interference with the subject’s daily activities. 
 
The relationship of an adverse event to the study intervention is defined as: 
Probable: Good reasons and sufficient documentation to assume a causal relationship 
Possible: A causal relationship is conceivable and cannot be dismissed 
Unlikely: The event is unlikely related to the study intervention 
 
A telephone enquiry hotline for reporting subject’s adverse events is available. The investigator 
will record all relevant information including signs and symptoms of the event, the onset time, 
the date of the event, the laboratory findings, concomitant drugs, and the outcome. All adverse 
events will be followed up until we have reached a defined outcome of the event, which can be 
one of the followings: (1) recovered with sequelae (for chronic conditions), (2) recovered, or 
(3) the management of the adverse event is taken over by another physician when the study 
ends. 
 
A clinical laboratory adverse event is any clinical laboratory abnormality that suggests a 
disease and/or organ toxicity is of sufficient severity that requires active intervention (i.e. 
change of dose, discontinuation of drug, more frequent follow-up or further investigation). An 
unscheduled visit will be performed if subjects have to withdraw early from the study. 
 
8.3 Serious adverse events 
A serious adverse event is an adverse event that results in one of the following outcomes: 
- 
Death 

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- 
Life-threatening 
- 
In-patient hospitalization or prolongation of existing hospitalization 
- 
A persistent or significant disability or incapacity 
- 
A congenital anomaly or birth defect 
 
The definitions of causal relationship to study intervention are the same as those for adverse 
events. We have a 24-hour on-call system to handle serious adverse events. The investigator 
will assess and treat the subjects as soon as possible. A standard serious adverse event form 
will be used (provided by the CREC at http://intranet.ccter.cuhk.edu.hk/sae/) to report the 
events within 24 hours after acknowledgement. We will arrange unscheduled follow-up visits 
immediately or within 24 hours on receiving the subject’s self-report of serious adverse events 
after the subjects have been discharged or if the subject has already been admitted to the 
hospital. Our investigators will assess the subject within 24 hours. The study team will record 
all relevant information including signs and symptoms of the event, the onset time, the date of 
the event, the laboratory findings, concomitant drugs, and the final outcome. A follow-up 
serious adverse event form will be sent within 14 days after submitting the initial serious 
adverse event form. Serious adverse events related to the study drug will be followed up until 
the subject has “recovered”, “recovered with sequelae” or “died”. SAE reports will be sent to 
our ethics committee. An unscheduled visit will be performed if subjects have to withdraw 
early from the study. 
 
8.4 Emergency contact person 
Dr. Jimmy Che-To Lai (Principal investigator) 
Tel: 3505-4205 
 
9. REFERENCES 
1. 
Toh MR, Wong EYT, Wong SH, Ng AWT, Loo LH, Chow PK, et al. Global 
Epidemiology and Genetics of Hepatocellular Carcinoma. Gastroenterology. 
2023;164(5):766-82. 
2. 
Yeh YP, Hu TH, Cho PY, Chen HH, Yen AM, Chen SL, et al. Evaluation of 
abdominal ultrasonography mass screening for hepatocellular carcinoma in Taiwan. 
Hepatology. 2014;59(5):1840-9. 
3. 
Brar G, Greten TF, Graubard BI, McNeel TS, Petrick JL, McGlynn KA, et al. 
Hepatocellular Carcinoma Survival by Etiology: A SEER-Medicare Database Analysis. 
Hepatol Commun. 2020;4(10):1541-51. 

BASS_HCC Study Protocol Version 1.1  
Page 14 of 16 
4. 
Goutte N, Sogni P, Bendersky N, Barbare JC, Falissard B, Farges O. Geographical 
variations in incidence, management and survival of hepatocellular carcinoma in a Western 
country. J Hepatol. 2017;66(3):537-44. 
5. 
Yang YM, Kim SY, Seki E. Inflammation and Liver Cancer: Molecular Mechanisms 
and Therapeutic Targets. Semin Liver Dis. 2019;39(1):26-42. 
6. 
Ringelhan M, Pfister D, O'Connor T, Pikarsky E, Heikenwalder M. The immunology 
of hepatocellular carcinoma. Nat Immunol. 2018;19(3):222-32. 
7. 
de Franchis R, Baveno VIF. Expanding consensus in portal hypertension: Report of 
the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal 
hypertension. J Hepatol. 2015;63(3):743-52. 
8. 
Ripoll C, Groszmann R, Garcia-Tsao G, Grace N, Burroughs A, Planas R, et al. 
Hepatic venous pressure gradient predicts clinical decompensation in patients with 
compensated cirrhosis. Gastroenterology. 2007;133(2):481-8. 
9. 
de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C, Baveno VIIF. Baveno 
VII - Renewing consensus in portal hypertension. J Hepatol. 2022;76(4):959-74. 
10. 
Kaplan DE, Bosch J, Ripoll C, Thiele M, Fortune BE, Simonetto DA, et al. AASLD 
practice guidance on risk stratification and management of portal hypertension and varices in 
cirrhosis. Hepatology. 2023. 
11. 
Colecchia A, Montrone L, Scaioli E, Bacchi-Reggiani ML, Colli A, Casazza G, et al. 
Measurement of spleen stiffness to evaluate portal hypertension and the presence of 
esophageal varices in patients with HCV-related cirrhosis. Gastroenterology. 
2012;143(3):646-54. 
12. 
Dajti E, Ravaioli F, Marasco G, Alemanni LV, Colecchia L, Ferrarese A, et al. A 
Combined Baveno VII and Spleen Stiffness Algorithm to Improve the Noninvasive 
Diagnosis of Clinically Significant Portal Hypertension in Patients With Compensated 
Advanced Chronic Liver Disease. Am J Gastroenterol. 2022;117(11):1825-33. 
13. 
Colecchia A, Ravaioli F, Marasco G, Colli A, Dajti E, Di Biase AR, et al. A 
combined model based on spleen stiffness measurement and Baveno VI criteria to rule out 
high-risk varices in advanced chronic liver disease. J Hepatol. 2018;69(2):308-17. 
14. 
Dajti E, Ravaioli F, Zykus R, Rautou PE, Elkrief L, Grgurevic I, et al. Accuracy of 
spleen stiffness measurement for the diagnosis of clinically significant portal hypertension in 
patients with compensated advanced chronic liver disease: a systematic review and individual 
patient data meta-analysis. Lancet Gastroenterol Hepatol. 2023;8(9):816-28. 
15. 
Zhang Y, Chen H, Chen S, Li W. Prognostic value of liver stiffness measurement in 
patients with hepatocellular carcinoma (HCC) treated by radiofrequency ablation: a meta-
analysis. Int J Hyperthermia. 2021;38(1):1052-9. 
16. 
Lee JI, Lee HW, Kim SU, Ahn SH, Lee KS. Follow-Up Liver Stiffness 
Measurements after Liver Resection Influence Oncologic Outcomes of Hepatitis-B-
Associated Hepatocellular Carcinoma with Liver Cirrhosis. Cancers (Basel). 2019;11(3). 
17. 
Marasco G, Colecchia A, Colli A, Ravaioli F, Casazza G, Bacchi Reggiani ML, et al. 
Role of liver and spleen stiffness in predicting the recurrence of hepatocellular carcinoma 
after resection. J Hepatol. 2019;70(3):440-8. 
18. 
Wu CW, Wong GL, Wong VW, Yam TF, Yip TC, Wong AC, et al. Baveno VII 
criteria identify varices needing treatment in patients with hepatocellular carcinoma of 
different Barcelona Clinic Liver Cancer stages. J Gastroenterol Hepatol. 2023;38(8):1381-8. 
19. 
Wu CW, Lui RN, Wong VW, Yam TF, Yip TC, Liu K, et al. Baveno VII Criteria Is 
an Accurate Risk Stratification Tool to Predict High-Risk Varices Requiring Intervention and 
Hepatic Events in Patients with Advanced Hepatocellular Carcinoma. Cancers (Basel). 
2023;15(9). 

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20. 
Allaire M, Campion B, Demory A, Larrey E, Wagner M, Rudler M, et al. Baveno VI 
and VII criteria are not suitable for screening for large varices or clinically significant portal 
hypertension in patients with hepatocellular carcinoma. Aliment Pharmacol Ther. 
2023;58(3):346-56. 
21. 
Gidener T, Dierkhising RA, Mara KC, Therneau TM, Venkatesh SK, Ehman RL, et 
al. Change in serial liver stiffness measurement by magnetic resonance elastography and 
outcomes in NAFLD. Hepatology. 2023;77(1):268-74. 
22. 
Stefanescu H, Marasco G, Cales P, Fraquelli M, Rosselli M, Ganne-Carrie N, et al. A 
novel spleen-dedicated stiffness measurement by FibroScan(R) improves the screening of 
high-risk oesophageal varices. Liver Int. 2020;40(1):175-85. 
23. 
Rigamonti C, Cittone MG, Manfredi GF, Sorge A, Moia R, Patriarca A, et al. High 
reproducibility of spleen stiffness measurement by vibration-controlled transient elastography 
with a spleen-dedicated module. Hepatol Commun. 2022;6(11):3006-14. 
24. 
Wong VW, Irles M, Wong GL, Shili S, Chan AW, Merrouche W, et al. Unified 
interpretation of liver stiffness measurement by M and XL probes in non-alcoholic fatty liver 
disease. Gut. 2019;68(11):2057-64. 
25. 
Paquet KJ. Prophylactic endoscopic sclerosing treatment of the esophageal wall in 
varices -- a prospective controlled randomized trial. Endoscopy. 1982;14(1):4-5. 
26. 
European Association for the Study of the Liver. Electronic address eee, European 
Association for the Study of the L. EASL Clinical Practice Guidelines on the management of 
hepatic encephalopathy. J Hepatol. 2022;77(3):807-24. 
27. 
Biggins SW, Angeli P, Garcia-Tsao G, Gines P, Ling SC, Nadim MK, et al. 
Diagnosis, Evaluation, and Management of Ascites, Spontaneous Bacterial Peritonitis and 
Hepatorenal Syndrome: 2021 Practice Guidance by the American Association for the Study 
of Liver Diseases. Hepatology. 2021;74(2):1014-48. 
28. 
Petta S, Sebastiani G, Vigano M, Ampuero J, Wai-Sun Wong V, Boursier J, et al. 
Monitoring Occurrence of Liver-Related Events and Survival by Transient Elastography in 
Patients With Nonalcoholic Fatty Liver Disease and Compensated Advanced Chronic Liver 
Disease. Clin Gastroenterol Hepatol. 2021;19(4):806-15 e5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

BASS_HCC Study Protocol Version 1.1  
Page 16 of 16 
Figure 1. Study design overview and study aims. (A) 159 patients with compensated 
liver disease and hepatocellular carcinoma (HCC) planning for curative treatment will 
undergo clinical assessment and blood tests, vibration-controlled transient 
elastography (VCTE) and oesophagogastroduodenoscopy (OGD). The current 
funding exercise will cover assessments at baseline and year 1, and we will obtain 
future funding for assessment at subsequent years. (B) We aim to validate serial 
monitoring of liver stiffness measurement (LSM) and platelet count (ie. Baveno VII 
criteria), and spleen stiffness measurement (SSM) in prediction of hepatic events 
(including high-risk varices) in compensated patients with HCC planning for curative 
treatment. (C) We also aim to determine whether serial monitoring of Baveno VII 
criteria and SSM predicts HCC recurrence. (D) Performance of 50Hz and 100Hz SSM 
module of VCTE will also be validated. (E) Finally, we will identify factors associated 
with hepatic events, HCC recurrence and mortality.