Reviewer ’s report  
 
Title: Hepatocellular carcinoma in Adult Thalassemia patients: An expert opinion based on  
current evidence  
 
Version: 0 Date: 27 Mar 2020  
 
Reviewer: Christos Kattamis  
 
Reviewer's report:  
 
 The review on HCC in adult thalassemia patients :An expert opinion  based on current 
evidence" prepared by a panel of specialists involved in diagnosis and management of patients 
with HCC and particular ly in patients wit b -thalassemia, with the main objectives to review and 
analyze 13 statements of major clinical importance in diagnosis and management of HCC. This 
precise review was prepared by a group of Italian specialists on HCC ,based on literature r eview 
and their extensive experience. .  
Reviewer's comments , remarks and proposals are addressed separately for each chapter.1. 
Abstract; line 7 . delete  " particularly".as other populations have higher frequencies . Proposal: 
Consider recent publication s on HCC in b -Thal patients,(1 V. De Sanctis et al; MJHID 
2020;21(1):e 202006n ;2.Papadopoulos A et al. MJHID 2020;12(1): e2020013; 3.Kourakli A et 
al; Blood 2018:132:2347).  
2.Background. line 8. Thalassemia; Define precisely the type of thalassemia of th e review. I 
assume that it  concern homozygous and double heterozygous patients with β and δβ or generally 
genetic defect of  genes of the β - chain genes cluster of adult Hbs A,F and A2. for which the term 
β-thalassemia can be used. Proposal :use the term of β-thalassemia all over the review.   line 10 
delete "particularly";  
line 20 Proposal: among the risk factors advanced age is also important!! Line 21; Term 
thalassemia intermedia should be also defined ; "what not regular transfusions means? Proposal; 
use the definition applied in Italy.  Line 58 ;SVR12:( define what number 12 means).   Line 59  it 
is stated that...the impact of iron overload in cirrhosis development will persist. Remark: To my 
opinion the f cirrhosis will be also decline as the young ge neration of patients follow  efficient 
chelation programs preserving a mild grade of iron overload. Next page.  line 2 change to "total 
b-thalassemia patients" not carriers .  
Line 3; Remark; Sentence not clear. Practical guidelines for β -thalassemia exists .!1l..  
MAIN BODY: Statement 1.line 18; Remark Recent data in Greece do not confirm the high 
(3.5%) prevalence of HCC in thalassemia.  
Statement 2: line 13 ; Proposal; Age of patients above 30 years  should also be consider for 
surveillance;  Line 33. Note : In Greece in 1992 the prevalence of ant -HCV positivity was 50% 
with 30 % of them HCV -RNA negative;  
Statement 3 Paragraph ( lines 24 -31) Comment; The presence of HCV infection in a good 
percentage of patients with TI indicates that these patients were tra nsfused rather frequently and 
that the percentage of TI  patients not requiring transfusion is low.     Statement 4.  lines 9 -11. 
Remark; To my opinion the statement that: "the residual risk of HCC in patients who attained 
SVR12 is related to iron overload " needs further studies. In our experience most of patients who 
attained  SVR12 ,especially with DAA, had normal or mild grade LIC  for before development 
of HCC.  
Statement 6. line 46 Question : even those who are immune and have antibodies?  MRI chapter; 
line 43 "may underestimate iron load"  change "to liver iron load" . next page line 3  "EMH a 
frequent feature in b -thalassemia"  propose to change to" in inefficiently transfused patients with 
TM and much more in patients with TI . Statement 7.  Remark: I dentify multidiscipline team  of 
specialists including a hematologist involved in the management of Thalassemic patients.'   
Statement 8 .line 53 Note: In our experience Pulmonary hypertension is more common in adult 
patients with TI not or inefficiently t ransfused This statement needs intense editorial revision for 
ease and better readability.  
Statements 9,10,11,and 12,need also careful editorial revision to improve readability and 
clarification ' In addition for statement 10 it is proposed to restrict th e case report to the main 
complications of heart and liver failure.  
General comments -proposals: I) Use the term b -thalassemia over the whole review. II) Consider 
recent publications on HCC in b -thalassemia III) consider the participation multidiscipline t eam 
of a hematologist.  IV) consider carefully editorial revision and English.    
 
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Not suitable for publication unless extensively edited  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding,  or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write  'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Acces s Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: Hepatocellular carcinoma in Adult Thalassemia patients: An expert opinion based on  
current evidence  
 
Version: 0 Date: 27 Mar 2020  
 
Reviewer: Christos Kattamis  
 
Reviewer's report:  
 
 The review on HCC in adult thalassemia patients :An expert opinion  based on current 
evidence" prepared by a panel of specialists involved in diagnosis and management of patients 
with HCC and particular ly in patients wit b -thalassemia, with the main objectives to review and 
analyze 13 statements of major clinical importance in diagnosis and management of HCC. This 
precise review was prepared by a group of Italian specialists on HCC ,based on literature r eview 
and their extensive experience. .  
Reviewer's comments , remarks and proposals are addressed separately for each chapter.1. 
Abstract; line 7 . delete  " particularly".as other populations have higher frequencies . Proposal: 
Consider recent publication s on HCC in b -Thal patients,(1 V. De Sanctis et al; MJHID 
2020;21(1):e 202006n ;2.Papadopoulos A et al. MJHID 2020;12(1): e2020013; 3.Kourakli A et 
al; Blood 2018:132:2347).  
2.Background. line 8. Thalassemia; Define precisely the type of thalassemia of th e review. I 
assume that it  concern homozygous and double heterozygous patients with β and δβ or generally 
genetic defect of  genes of the β - chain genes cluster of adult Hbs A,F and A2. for which the term 
β-thalassemia can be used. Proposal :use the term of β-thalassemia all over the review.   line 10 
delete "particularly";  
line 20 Proposal: among the risk factors advanced age is also important!! Line 21; Term 
thalassemia intermedia should be also defined ; "what not regular transfusions means? Proposal; 
use the definition applied in Italy.  Line 58 ;SVR12:( define what number 12 means).   Line 59  it 
is stated that...the impact of iron overload in cirrhosis development will persist. Remark: To my 
opinion the f cirrhosis will be also decline as the young ge neration of patients follow  efficient 
chelation programs preserving a mild grade of iron overload. Next page.  line 2 change to "total 
b-thalassemia patients" not carriers .  
Line 3; Remark; Sentence not clear. Practical guidelines for β -thalassemia exists .!1l..  
MAIN BODY: Statement 1.line 18; Remark Recent data in Greece do not confirm the high 
(3.5%) prevalence of HCC in thalassemia.  
Statement 2: line 13 ; Proposal; Age of patients above 30 years  should also be consider for 
surveillance;  Line 33. Note : In Greece in 1992 the prevalence of ant -HCV positivity was 50% 
with 30 % of them HCV -RNA negative;  
Statement 3 Paragraph ( lines 24 -31) Comment; The presence of HCV infection in a good 
percentage of patients with TI indicates that these patients were tra nsfused rather frequently and 
that the percentage of TI  patients not requiring transfusion is low.     Statement 4.  lines 9 -11. 
Remark; To my opinion the statement that: "the residual risk of HCC in patients who attained 
SVR12 is related to iron overload " needs further studies. In our experience most of patients who 
attained  SVR12 ,especially with DAA, had normal or mild grade LIC  for before development 
of HCC.  
Statement 6. line 46 Question : even those who are immune and have antibodies?  MRI chapter; 
line 43 "may underestimate iron load"  change "to liver iron load" . next page line 3  "EMH a 
frequent feature in b -thalassemia"  propose to change to" in inefficiently transfused patients with 
TM and much more in patients with TI . Statement 7.  Remark: I dentify multidiscipline team  of 
specialists including a hematologist involved in the management of Thalassemic patients.'   
Statement 8 .line 53 Note: In our experience Pulmonary hypertension is more common in adult 
patients with TI not or inefficiently t ransfused This statement needs intense editorial revision for 
ease and better readability.  
Statements 9,10,11,and 12,need also careful editorial revision to improve readability and 
clarification ' In addition for statement 10 it is proposed to restrict th e case report to the main 
complications of heart and liver failure.  
General comments -proposals: I) Use the term b -thalassemia over the whole review. II) Consider 
recent publications on HCC in b -thalassemia III) consider the participation multidiscipline t eam 
of a hematologist.  IV) consider carefully editorial revision and English.    
 
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Not suitable for publication unless extensively edited  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding,  or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write  'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Acces s Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Hepatocellular carcinoma in Adult Thalassemia patients: An expert opinion based on  
current evidence  
 
Version: 0 Date: 27 Mar 2020  
 
Reviewer: Christos Kattamis  
 
Reviewer's report:  
 
 The review on HCC in adult thalassemia patients :An expert opinion  based on current 
evidence" prepared by a panel of specialists involved in diagnosis and management of patients 
with HCC and particular ly in patients wit b -thalassemia, with the main objectives to review and 
analyze 13 statements of major clinical importance in diagnosis and management of HCC. This 
precise review was prepared by a group of Italian specialists on HCC ,based on literature r eview 
and their extensive experience. .  
Reviewer's comments , remarks and proposals are addressed separately for each chapter.1. 
Abstract; line 7 . delete  " particularly".as other populations have higher frequencies . Proposal: 
Consider recent publication s on HCC in b -Thal patients,(1 V. De Sanctis et al; MJHID 
2020;21(1):e 202006n ;2.Papadopoulos A et al. MJHID 2020;12(1): e2020013; 3.Kourakli A et 
al; Blood 2018:132:2347).  
2.Background. line 8. Thalassemia; Define precisely the type of thalassemia of th e review. I 
assume that it  concern homozygous and double heterozygous patients with β and δβ or generally 
genetic defect of  genes of the β - chain genes cluster of adult Hbs A,F and A2. for which the term 
β-thalassemia can be used. Proposal :use the term of β-thalassemia all over the review.   line 10 
delete "particularly";  
line 20 Proposal: among the risk factors advanced age is also important!! Line 21; Term 
thalassemia intermedia should be also defined ; "what not regular transfusions means? Proposal; 
use the definition applied in Italy.  Line 58 ;SVR12:( define what number 12 means).   Line 59  it 
is stated that...the impact of iron overload in cirrhosis development will persist. Remark: To my 
opinion the f cirrhosis will be also decline as the young ge neration of patients follow  efficient 
chelation programs preserving a mild grade of iron overload. Next page.  line 2 change to "total 
b-thalassemia patients" not carriers .  
Line 3; Remark; Sentence not clear. Practical guidelines for β -thalassemia exists .!1l..  
MAIN BODY: Statement 1.line 18; Remark Recent data in Greece do not confirm the high 
(3.5%) prevalence of HCC in thalassemia.  
Statement 2: line 13 ; Proposal; Age of patients above 30 years  should also be consider for 
surveillance;  Line 33. Note : In Greece in 1992 the prevalence of ant -HCV positivity was 50% 
with 30 % of them HCV -RNA negative;  
Statement 3 Paragraph ( lines 24 -31) Comment; The presence of HCV infection in a good 
percentage of patients with TI indicates that these patients were tra nsfused rather frequently and 
that the percentage of TI  patients not requiring transfusion is low.     Statement 4.  lines 9 -11. 
Remark; To my opinion the statement that: "the residual risk of HCC in patients who attained 
SVR12 is related to iron overload " needs further studies. In our experience most of patients who 
attained  SVR12 ,especially with DAA, had normal or mild grade LIC  for before development 
of HCC.  
Statement 6. line 46 Question : even those who are immune and have antibodies?  MRI chapter; 
line 43 "may underestimate iron load"  change "to liver iron load" . next page line 3  "EMH a 
frequent feature in b -thalassemia"  propose to change to" in inefficiently transfused patients with 
TM and much more in patients with TI . Statement 7.  Remark: I dentify multidiscipline team  of 
specialists including a hematologist involved in the management of Thalassemic patients.'   
Statement 8 .line 53 Note: In our experience Pulmonary hypertension is more common in adult 
patients with TI not or inefficiently t ransfused This statement needs intense editorial revision for 
ease and better readability.  
Statements 9,10,11,and 12,need also careful editorial revision to improve readability and 
clarification ' In addition for statement 10 it is proposed to restrict th e case report to the main 
complications of heart and liver failure.  
General comments -proposals: I) Use the term b -thalassemia over the whole review. II) Consider 
recent publications on HCC in b -thalassemia III) consider the participation multidiscipline t eam 
of a hematologist.  IV) consider carefully editorial revision and English.    
 
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Not suitable for publication unless extensively edited  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding,  or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write  'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Acces s Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant