Research Article ISSN 2833-0390

International Journal of Research in Oncology

Global Assessment of Predictive Biomarkers in Malian BCLC Stage C

Hepatocellular Carcinoma Patients under Mono or Combination Immune
Checkpoint Inhibitors Treatment: A Proposed Research Protocol
Keїta Kaly1, Keїta Abdoulaye2, Diawara Abdoulaye3,4, Koné Abdouramane Alou5, Bathily Moussa5,
Dembélé Abdoul Karim5,6, Sidibé Mariam5, Coulibay Aissata7, Kamaté Bakarou7, Traoré Cheick
Bougadari7, Wélé Mamadou3,4, Traoré Kassim8, Dabitao Djénéba9,10, Samassekou Oumar11, Soukho
Assetou Kaya1,10, Traoré Abdel Kader10, and Diakité Mahamadou10,12,13
1
Department of Internal Medicine at the University Hospital Center
of the Point G, Bamako, Mali.
Drug and Laboratory Unit, Regional Health Department of
2

Koulikoro, Mali.
3
Institute of Applied Sciences (ISA), Bamako, Mali.
4
Faculty of Sciences and Techniques (FAST), Bamako, Mali.
Department of Hematology and Medical oncology at the University
5

Hospital Center of the Point G, Bamako, Mali.

Center for Research and Control of Sickle Cell Disease, Bamako, Mali.
6 *
Correspondence:
Dr. Keïta Kaly, Department of Internal Medicine at the
7
Department of anatomo-pathology at the University Hospital Center University Hospital Center of the Point G, Bamako, Mali, Tel:
of the Point G, Bamako, Mali. (00223)66998767; E-mail: [email protected].
Campbell University, Buies Creek, North Carolina, United States of
8

America. Received: 22 Feb 2023; Accepted: 25 Mar 2023; Published: 29 Mar 2023
ImmunoCore Laboratory, University Clinical Research Center, Point
9

G, Bamako, Mali.
10
Faculty of Medicine and Odontosomatology (FMOS), Bamako, Mali.
Division of Genetics, Department of Pediatrics, Faculty of Medicine
11

and Health Sciences, Université de Sherbrooke, Quebec, Canada.

University of Clinical Research Center (UCRC) at the University
12

Hospital Center of the Point G, Bamako, Mali.

13
Malaria Research and Training Center, Bamako, Mali.

Citation: Keїta K, Keїta A, Diawara A, et al. Global Assessment of Predictive Biomarkers in Malian BCLC Stage C Hepatocellular
Carcinoma Patients under Mono or Combination Immune Checkpoint Inhibitors Treatment: A Proposed Research Protocol. Int J Res
Oncol. 2023 2(1): 1-6.

ABSTRACT
Background: According to the Barcelona Clinic Liver Cancer (BCLC) staging system, only the advanced stage (stage C) hepatocellular carcinoma
(HCC) patient is eligible for systemic treatments. In addition to sorafenib and lenvatinib that represent the standard-of-care options in the first-line
treatment, the multikinase inhibitors regorafenib and cabozantinib or ramucirumab, the anti-vascular-endothelial growth factor-2 (VEGF-R2) in
the second-line setting but their poor tolerability have brought out the need for new therapeutic strategies, the immune checkpoint inhibitors (ICIs)
might represent the most important novelty and the future perspective also in the field of HCC. Therefore, the need to identify predictive biomarkers
to select those patients who might actually benefit from ICIs-based treatment is urgently a challenge. Our central hypothesis is that the global
assessment of predictive biomarkers could help patient-specific choices for ICIs treatment by developing simplified therapeutic algorithms and novel
prognostic index for efficient HCC management. The primary aim of this work will be to globally assess predictive biomarkers in Malian patients
with BCLC stage C HCC undergoing treatment with ICIs in mono or in combination.

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 Method/Design: To assess hematogical, biochemical, immunohistological, epigenetical, genetical and neoantigenic predictive biomarkers in
Malian BCLC stage C HCC cohort, we are going to conduct a national and multi-centre cohort study with prospective data collection during the
study period between January 1, 2024 to December 31, 2026. All consented patient with BCLC stage C HCC treated with sorafenib or ICIs in first
line or second line therapy during a study period will be included. Potential participants will be screened for eligibility criteria and after obtaining
well-informed written consent. The participants will be distributed in 1: 1 manner into experimental group/group A (ICIs mono or combination
therapy with first or second line) and control group/group B (Sorafenib in first line).

Discussion: This cohort study will the potential to make an important contribution to increase the knowledge on predictive biomarkers associated
to clinical responses outcomes, immune-related adverse events and others evolutionary outcomes in-patient with HCC under ICIs treatment.

Keywords Additionally, the authorization was recent in the majority of cases,

Research protocol, Predictive biomarkers, Immune checkpoint even though, we have a very few data (or no one in some cases)
inhibitors, Hepatic carcinoma cancer, Africa. regarding the phase IV, as well as real life data from the every-day
clinical practice [9].
Background
Primary liver cancer is the sixth most commonly diagnosed cancer Indeed, Numerous studies on predictive biomarkers in various
and the third leading cause of cancer death worldwide in 2020, with cancers treatment with ICIs such immune cell infiltration,
approximately 906,000 new cases and 830,000 deaths [1]. Primary peripheral blood analyses, PD-L1 overexpression, copy number
liver cancer includes hepatocellular carcinoma (HCC) (comprising alterations, neoantigen clonality, mutational landscape, mismatch-
75%-85% of cases) and intrahepatic cholangiocarcinoma (10%- repair deficiency, transcription factors, and miRNA were
15%), as well as other rare types [1]. The main risk factors for HCC performed [9-16].
are chronic infection with hepatitis B virus (HBV) or hepatitis C
virus (HCV), aflatoxin-contaminated foods, heavy alcohol intake, Despite, literature data on predictive biomarkers in patients with
excess body weight, type 2 diabetes, and smoking [2]. In Mali, in advanced HCC under ICIs remain insufficient to propose a patient-
2020, liver cancer is the fourth most frequently diagnosed cancer specific choice for ICIs treatment and even to develop simplified
and the fourth leading cause of cancer death, with an estimated 727 therapeutic algorithms and novel prognostic index for efficient
new cases and 684 deaths [3,4]. HCC management.

Regarding diagnostic and therapeutic strategy of HCC, the Although, the biotherapy is progressively invited in the therapeutic
Barcelona Clinic Liver Cancer (BCLC) is the one of more staging arsenal of inflammatory diseases, especially HCC in Africa and
systems used. It consist five stages for the disease: patients with particularly in Mali where global assessment of hematogical,
early HCC (stage 0/A) who are candidates for curative-intent radical biochemical, immunohistological, epigenetical, genetical and
therapies such as resection, liver transplantation and ablation; neoantigenic predictive biomarkers associated to therapeutic
patients with multinodular tumours (stage B, intermediate) and efficacy, ICIs toxicities, and others evolutionary (partial remission,
candidate to local treatment, such as chemoembolization; those progression-free survival, overall survival, relapsed cases, and
in advanced stage (stage C), eligible for systemic treatments and deaths) outcomes in HCC patient constitute almost a virgin ground.
patients in terminal stage (stage D) for whom palliative cares are
recommended [5]. Thus, a global assessment of predictive biomarkers in patients
with advanced HCC under ICIs compared to those under empirical
In addition to tyrosine kinase inhibitors, multikinase inhibitors sorafenib 200 mg therapy could allow the identification of relevant
and anti-vascular-endothelial growth factor-2 (VEGF-R2), the predictive biomarkers associated with therapeutic efficacy and
systemic management of HCC has been revolutionized by the immune-related adverse events (irAEs), and the development of
advent of immune checkpoint inhibitors (ICIs), a therapeutic class a simplified therapeutic algorithms and novel prognostic index
of monoclonal antibodies that blocks the immune checkpoints. helping in patient selection and decision making by distinguishing
These are co-inhibitory molecules physiologically expressed in responders and non-responders.
different cells types, such as natural killer cells, dendritic cells,
tumor-associated macrophages, monocytes and myeloid-derived In Mali, none study has assesses predictive biomarkers especially
suppressor cells (MDSCs)—including B and T cells, and that from patients with advanced HCC on ICIs. Here, there are some
mantains self-tolerance. ICIs act by applying a break that prevent laboratories skills with high training specialist for hematological,
the activation of these cells, limiting tissue damage. The main biochemical, immunohistochemical tests but genetic and
immune checkpoint receptors are CTLA-4, PD-1, TIM-3, BTLA, epigenetic approaches knowing some difficulties. In order to
VISTA, LAG-3 and OX-40. In this field, two classes of ICIs are assess overall predictive biomarkers, such project can helping for
currently being tested as mono or combination therapies: CTLA-4 determine the prevalence of patients with advanced HCC on ICIs,
(tremelimumab and ipilimumab) and PD-1/PD-L1 inhibitors (anti- relevant predictive associated to therapeutic response and irAEs,
PD-1: nivolumab, pembrolizumab, tislelizumab, camrelizumab built Malian robust oncology team and further Cancer training and
and sintilimab; anti PD-L1: atezolizumab and durvalumab) [6-9]. research center in perspective.
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The primary aim of this work will be to globally assess predictive period will be included. Will not be included in this study, others
biomarkers in Malian patients with BCLC stage C HCC BCLC stage of HCC than BCLC stage C hepatocellular carcinoma;
undergoing treatment with immune checkpoint inhibitors in under others treatment regimens for BCLC stage C hepatocellular
mono or in combination. The specific aims will be: i. to describe carcinoma other than sorafenib and ICIs; outside the study period;
sociodemographic aspects of a study population; ii. to determine outside the study sites.
the clinical presentation of a study population; iii. to class our HCC
patients according to the Barcelona Clinic Liver Cancer staging Recruitment and allocation
system; iv. to describe therapeutic and follow up aspects of a study Potential participants will be screened for eligibility criteria and
population; v. to identify predictive biomarkers associated to after obtaining well-informed written consent, it will be recruited
clinical responses; vi. to identify predictive biomarkers associated as a participant. The participants will be distributed in 1: 1 manner
to irAEs; vii. to put in place a biobank for adequate investigation. into experimental group/group A (ICIs mono or combination
therapy with first or second line) and control group/group B
Method (Sorafenib in first line) (Figure 1). ICIs may be ipilimumab 5
Setting/location milligrams per milliliter (Ipilimumab 3 mg/kg IV immediately
The Hemato-oncology and internal medicine department at the following nivolumab 1 mg/kg IV on the same day, q3Weeks for 4
University Hospital Center of the Point G and oncology department doses; after completing 4 doses of combination therapy, continue
at the Hospital Luxembourg Mother and child Hospital will serve nivolumab as a single-agent until intolerable toxicity or disease
as the place of recruitment of patients. These hospitals treat cancer progression) [18] and nivolumab 10 milligrams per milliliter
cases in Mali. The anatomopathology department at the University (Nivolumab 1 mg/kg IV q3Weeks PLUS Ipilimumab 3 mg/
Hospital Center of the Point G will conduct immunohistochemical kg IV on the same day for 4 doses; after completing 4 doses of
examination especially HCC diagnosis. Hematological and combination therapy: Administer nivolumab 240 mg IV q2Weeks
biomedical laboratory unit of Univesity Clinical Research Center or 480 mg IV q4Weeks; continue until disease progression or
(UCRC), well-epuiped with well-trained biologist, will serve to unacceptable toxicity) [19]. Sorafenib 200 milligrams is indicated
carry out hematological and biochemical tests. For immunological for unresectable hepatocellular carcinoma with
tests such flow cytometry, immunology unit of SEROFO is able
to carry out it. For genetic and epigenetic tests, foreign laboratory 400 mg PO q12hr; if skin toxicity, discontinue/decrease dose
will be solicited. frequency to qDay or every other day as recommended by
Manufacturer [20].
Study Design
To assess hematogical, biochemical, immunohistological, Figure 1: Shows the study procedure in the form of a flow chart
epigenetical, genetical and neoantigenic predictive biomarkers in
Malian BCLC stage C HCC cohort, we are going to conduct a
national and multi-centre study with prospective data collection
from patients with BCLC stage C HCC during the study period
between January 1, 2024 to December 31, 2026, i.e. 3 years.

Sampling
This will be an exhaustive sampling of all patients with BCLC
stage C HCC during the study period. All diagnosed liver cancer
will be classified according to the Barcelona Clinic Liver Cancer
staging system.

Sample size calculation

For the estimation of the prevalence rate of HCC in a national,
multi-center, and prospective study, we will use the calculation of
the minimum sample size using the following formula: n= [z2*p(1-p)] /
e2
/ 1 + [z2*p(1-p)] / e2*N]. The confidence interval is 95%, i.e. Z= 1.96. The
hospital prevalence of HCC in Mali is 5, 1% [17], which implies
that Z2 = 0.95. The population of Mali, i.e. 20,250,834 inhabitants. Study procedure: Assessments and data collection
With a choice of margin of error at 5%, which is 0.05, a minimum
sample size of 74, 4 was calculated. Attrition rate of 10% was The study design and assessment plan is summarized in Figure 1.
incorporated in the calculation and sample size was estimated at Part 1 of the study will permit to recruit, allocated participants,
82 participants in each group. and to start follow-up with predictive biomarkers data collection,
management and analysis from the 82 eligible subjects of each
Eligibility Criteria group during 1 years. Part 2 correspond of the end of recruitment
All consented patient with BCLC stage C HCC treated with and allocation and continuing follow-up until M24 from the
sorafenib or ICIs in first line or second line therapy during a study last recruited participant. And this part 2 of the study will focus
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on genetic, epigenetic and neoantigenic data management and Mutational and Neoantigenic data X X
analysis. It will last 2 years. neoantigen-expressing tumor clones X X
clonal mutations in neoantigens X X
Both parts of the study follow the same planned protocol schedule mismatch-repair deficiency X X
others X X
consisting of a baseline visit followed by seven consecutive visits
Genetic data X X
(Baseline visit, M3, M6, M9, M12, M15, M18, M21, and M24
overexpression of IGK, GBP1, STAT1, IGLL5,
visits), plus additional unscheduled visits in the event of HCC X X
and OCLN
complications. overexpression of immune-related peptides
X X
expanding pre-existing T cells
Sociodemographical and clinical assessments, sampling for copy number alterations (CAN) of PD-L1 and
X X
PD-L2
laboratory assessments and therapeutic responses and evolutionary
others X X
outcomes are to be performed at specified visits, as shown in table Epigenetical data X X
1. methylation pattern of PD-L1 and CTLA-4 X X
serum levels of miRNA X X
Table 1: Schedule of variable assessment during follow-up. others X X
Baseline Follow- TTherapeutic data X X
Assessments
visits up Regimen of first-line with Sorafenib or ICIs in
X X
Sociodemographic data X monotherapy
age X Regimen of second-line with ICIs combination X X
sex X Evolutionary data X X
profession X Partial remission X X
ethnicity X Complete remission X X
Clinical data X X ICIs related-adverses events X X
physiological personal history X Sorafenib related-adverses events X X
pathological personal and familial history X progression-free survival X X
physical examination findings X X overall survival X X
ECOG PS scale X relapsed cases X X
Child-Pugh scale X deaths X X
BCLC findings X
others X X Definitions
Immuno-hematological data (hemogram or flow Some conditions and outcomes are defined in the table 2.
X X
cytometry)
lymphocytes (CD4+, CD8+) X X
Table 2: Definitions of conditions and outcomes.
B Cells (CD20+) X X
Conditions/outcomes Definitions
lymphocytes (CD134+, CD137+, and FOXP3+) X X
Advanced stage; preserved liver function; ECOG
natural killer cells (NKp46+) X X BCLC staging system in
PS: 1 – 2; Child Pugh: A – B; macrovascular
peripheral blood absolute lymphocyte count X X HCC
invasion or extrahepatic spread.
absolute eosinophil count; relative lymphocyte count X X First-line therapy of Tyrosine kinase inhibitors (sorafenib) or ICIs
circulating tumor cells X X BCLC stage C HCC monotherapy (Ipilimumab + Nivomumab)
number of activated T cells (CD134+, CD137+, and ICIs combination (Ipilimumab + Nivomumab)
X X Second-line of BCLC
FOXP3+) indicate if irAEs or non-responders to first-line
stage C HCC
monocytes (CD16+ and CD68+) X X therapy
CD8+PD-1hiCTLA-4hi and CD4+FOXP3-PD-1hi
X X
subpopulations Biosampling
myeloid-derived suppressor cells X X
Biosampling will take place at inclusion and after 12 and 24 months.
others X X
Blood samples will be collected at these times. All samples will be
Biochemical data X X
processed immediately according to a standardized protocol. All
LDH level X X
samples will be frozen at −80°C and stored at the Liquid Biobank
others X X
(LBB, www.biobankenbern.ch), Inselspital, Bern, until further
Immuno-histological data X X
analysis in batches. The following parameters will be examined:
tumor-infiltrating lymphocyte (CD4+, CD8+) X X
Basal level expression of PD-L1 X X
hematological, biochemical, immunohistochemical, and especially
IFN-γ signaling in CD8+ T cells X X
genetic, epigenetic and neoantigenic predictive biomarkers.
PD-L1 copy number gain X X
expression of IDO X X Outcomes
Th1-associated markers X X Primary Outcome Measures
ICOS pathway X X Primary outcomes will be hematogical, biochemical,
others X X immunohistological, epigenetical, genetical and neoantigenic
predictive biomarkers associated to clinical responses, ICIs
Int J Res Oncol, 2023 Volume 2 | Issue 1 | 4 of 6
toxicities, and others evolutionary (partial remission, progression- consent of all participants will be obtained.
free survival, overall survival, relapsed cases, and deaths) outcomes.
These predictive biomarkers will be measured by hemogram, flow Discussion
cytometry, biochemical test, immunohistochemical examination, Among BCLC staging system, only the advanced stage (stage C)
exploring epigenetic, genetic and neoantigenic tests. A structured HCC patient is eligible for systemic treatments. Indeed, according
questionnaire on the clinical responses, ICIs toxicities and to international guidelines, sorafenib and lenvatinib represent the
evolutionary outcomes will be administered. standard-of-care options in the first-line treatment, the multikinase
inhibitors regorafenib and cabozantinib or ramucirumab, the
Secondary Outcome Measures anti-vascular-endothelial growth factor-2 (VEGF-R2), are the
Secondary outcomes will be the characterization the socio- main choices in the second-line setting but their poor tolerability
demographic, clinical, therapeutic and evolutionary aspects and have brought out the need for new therapeutic strategies. In this
the novel predictive biomarkers of patients with BCLC stage C context, the immune checkpoint inhibitors (ICIs) might represent
HCC identified because of cross-sectional analysis between these the most important novelty and the future perspective in the field
aspects and predictive biomarkers. A structured questionnaire of HCC. Therefore, the need to identify predictive biomarkers to
on these aspects will be administered and predictive biomarkers select those patients who might actually benefit from ICIs-based
measurement as stipulated below will be done. treatment is urgently a challenge [4,9].

Data Management and Analysis Detailed information on predictive biomarkers specifically in stage
Database C HCC patients remains scarce. These data are often derived from
All data from this cohort study will be collected electronically using outside Africa and are not multidimensional approaches notably
a dedicated central electronic data capturing system (REDCap). assessing globally the predictive biomarkers in these patients.
All structured questionnaires will be distributed as online surveys
and directly entered electronically into the database. This cohort study will the potential to make an important
contribution to increase the knowledge on predictive biomarkers
Data Management associated to therapeutic efficacy, IrEAs and others evolutionary
Data will be extracted under strict confidential measures, outcomes in patient with HCC under ICIs. Our study will differ
anonymised and will be accessible to only research supervisors from previous studies by assessing globally the predictive
during the data extraction process. The extracted data will be biomarkers whose the well-conducted cross-sectional analysis
captured and saved into a password-protected Microsoft Access could provide novel relevant predictive biomarkers, simplified
2016 database with the password known to only persons responsible therapeutic algorithm, and novel prognostic index development;
for data capturing and the principal investigators. Data capturing and by holding in Africa particularly in Mali where predictive
will be managed and coordinated by a dedicated data manager who biomarkers especially in BCLC stage C HCC patient constitute
checks all captured data for correctness. The finalised database
almost virgin ground. To address the complexity of the study,
will be stored in a secured electronic system and backed-up on a
this study will be supported by a large team of experts in different
dual-core electronic processor. Then it will be exported into SPSS
fields, and has national and international collaborations.
version 22 software for analysis.
As this study addresses the evolution of stage C HCC patient under
Data Analysis
ICIs, a limitation will be the national recruitment, which does not
To detect a positive correlation between predictive biomarkers
allow generalization of our data. We are exploring a future study
and clinical responses, irAEs and others outcomes, a cross-
to fill this gap and to provide an additional multi-country study.
sectional analysis (comparison between patients and controls of
data acquired during the follow-up) of continuous variables will
The results of this study are expected to change current therapeutic
be done with Student’s t test or analysis of variance or in case of
approach in BCLC stage C HCC patient by focusing on patient-
skewed distributions which cannot be normalized corresponding
specific choice of ICIs after assessing globally the predictive
nonparametric tests will be used. Chi-squared and fisher’s exact
biomarkers, improve stage C HCC patient prognosis, provide
tests will be used for cross-sectional analysis of categorical
novel predictive biomarkers, and to implement the biobank in Mali
variables. The relative risk (hazards ratios) will be calculated with
so that to pursue investigation for predictive biomarkers by others
their corresponding 95% confidence intervals and alpha level of
protocols or by others researcher.
0.05 will be applied as the criterion for statistical significance.
Quantitative data will be presented as means and standard
deviation; and qualitative data will be expressed as numbers and References
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© 2023 Keїta K, et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License

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