Title: The fate of indeterminate liver lesions: what proportion are precursors of hepatocellular
carcinoma?
Version: 2 Date: 12 Nov 2021
Reviewer's report:
SPECIFIC COMMENTS
This manuscript is pleasurable and flowing, in general; no major issues are appreciable.
Although language used is appropriate, I (I am not a native English speaker) recommend to
Authors to obtain a certified native speaker with proficiencies in the scientific-medical field to
complete properly this paper (if not jet done). Moreover, I recommend making a further revision
of the manuscript to fix some typing/language errors. For example: “Abstract Background: The
natural history and incidence of hepatocellular carcinoma (HCC) arising from indeterminate
liver lesions is not well characterised.”. evaluate the possibility to change with established.
TITLE
The title is clear and direct. Personally, I believe it could be improved, for example: “The fate
of indeterminate liver lesions: what proportion are precursors of hepatocellular carcinoma? A
retrospective follow-up study”. I suggest removing the last sentence. If the editor agrees, the
authors could consider the change of the title.
ABSTRACT
The abstract is well structured in all its section and, therefore, it properly reflects the main text,
highlighting the most important aspects of this paper. However, some adjustments are needed.
For example: English language and the last sentence in the conclusions: “Our data support a
strategy of enhanced surveillance in patients with indeterminate lesions.”. the aim of the study
and the methodology used did not support this conclusion. This is a secondary consequence that
need a direct and strong demonstration.
KEYWORDS
Authors did not correctly report all keywords from MeSH Browser. In particular I checked
“Indeterminate liver lesions” and “Chronic liver disease” on MeSH Browser and I did not find
these KWs. This is important, in my personal opinion, in order to increase the traceability of this
paper (and consequently the possibility of the Journal to be cited by Readers and Stakeholders).
I suggest the check of the all KWs.
INTRODUCTION
Although the introduction fits the context of the study, it could be improved. In fact, many
concepts clearly explicated in an exhaustive introduction could help readers to become
passionate about reading the paper and using it as a reference.
First of all, in the background, from line 74 to line 77 the Authors referred to MRI without
specifying the type of contrast media. In fact, there are many diagnostic improvements using Gd-
EOB-DTPA MRI, as reported in other published paper such as J Gastroenterol Hepatol. 2016
Jan;31(1):69-80. doi: 10.1111/jgh.13150. PMID: 26312574. Please, could the Author fix this
point and cite this article? Furthermore, in the background, from line 74 to line 77 the Authors
stated that: “Lesions do not always demonstrate the characteristic radiological features of HCC
(arterial enhancement, and venous phase washout and / or delayed phase washout) [1, 10], or of
any other known liver lesions, and such lesions are therefore classified as indeterminate. These
indeterminate lesions are commonly seen in clinical practice, usually in cirrhotic patients, posing
a diagnostic and prognostic dilemma for clinicians as there are no clear guidelines describing
their significance and management.”. for lesions >1 cm, with no typical imaging findings
(after two or also after only one imaging technique), the guidelines recommend to perform
biopsy. Unfortunately, biopsy is not always performable, and biopsy could produce different
complications. Please, the author could analyze this theme of biopsy, its rate of feasibility and
the need to a noninvasive method to characterize a liver nodule.
MATERIALS & METHODS
It is mandatory to report informations regard the MRI. Which machine? Which contrast media?
Furthermore, it is important to understand if the cases enrolled in this paper as indeterminate
were correctly diagnosed. For example, in the scenario of the response evaluation criteria,
it is well known that the decision on whether a HCC patient is a responder or progressor
after treatment may vary among different radiologists, especially in case of a non-specifically
trained radiologist and, therefore, regardless of the adopted criteria, patients should be
evaluated by experienced radiologists to minimize variability in this critical instance [Eur
Radiol. 2018;28(9):3611-3620. doi:10.1007/s00330-018-5393-3]. Please, could the Authors
report the methodology used (one or more experienced radiologist evaluated MRI?) citing the
aforementioned paper [Eur Radiol. 2018;28(9):3611-3620. doi:10.1007/s00330-018-5393-3].
Moreover, did the authors re-evaluate the imaging of lesions included in the study?
Which version of LI-RADS was used?
Who applied the LI-RADS?
It is important to report why these lesions you enrolled did not undergo BIOPSY.
RESULTS
Results remain clear and well-structured, and no further adjustments are needed.
DISCUSSION
Page 9, line 239: “Our analysis of progression to HCC based on baseline LI-RADS score
showed increasing incidence with increasing score, but our rates were lower than those recently
reported in an American study [16].”. please, the Authors explain the reason for these different
results. In fact, LIRADS has many limitations and no significant improvement in the diagnostic
performance compared with easl in different setting as reported by many published papers
(Liver Int. 2021 Jul 9. doi: 10.1111/liv.15012. Epub ahead of print. PMID: 34242468.  --
Eur J Gastroenterol Hepatol. 2019 Mar;31(3):283-288. doi: 10.1097/MEG.0000000000001269.
PMID: 30234643.).
In my opinion, the authors should emphasize the value of their idea. For example they could
write: “In the era of tailored medicine, such as in other experience like the management of
adverse events with tailored sorafenib dosing that prolongs survival of hepatocellular carcinoma
patients [J Hepatol. 2019;71(6):1175-1183. doi:10.1016/j.jhep.2019.08.015], the results of our
study could help the hepatologists by offering an easy to use tool to identify the patients who
benefit from a tailored surveillance in terms of time and type of imaging (MRI) to use.”.
In the limitation section, it is important to report a limit (if the authors will not improve their
paper with this data): the study did not evaluate if the HCC diagnosed in the study period comes
from an indeterminate nodule. This type of analysis it will be a matter of investigation for a
further study.
TABLES & FIGURES
Tables & Figures are satisfactory, and they correctly match the quality standard of this Journal.
Title: The fate of indeterminate liver lesions: what proportion are precursors of hepatocellular
carcinoma?
Version: 2 Date: 12 Nov 2021
Reviewer's report:
SPECIFIC COMMENTS
This manuscript is pleasurable and flowing, in general; no major issues are appreciable.
Although language used is appropriate, I (I am not a native English speaker) recommend to
Authors to obtain a certified native speaker with proficiencies in the scientific-medical field to
complete properly this paper (if not jet done). Moreover, I recommend making a further revision
of the manuscript to fix some typing/language errors. For example: “Abstract Background: The
natural history and incidence of hepatocellular carcinoma (HCC) arising from indeterminate
liver lesions is not well characterised.”. evaluate the possibility to change with established.
TITLE
The title is clear and direct. Personally, I believe it could be improved, for example: “The fate
of indeterminate liver lesions: what proportion are precursors of hepatocellular carcinoma? A
retrospective follow-up study”. I suggest removing the last sentence. If the editor agrees, the
authors could consider the change of the title.
ABSTRACT
The abstract is well structured in all its section and, therefore, it properly reflects the main text,
highlighting the most important aspects of this paper. However, some adjustments are needed.
For example: English language and the last sentence in the conclusions: “Our data support a
strategy of enhanced surveillance in patients with indeterminate lesions.”. the aim of the study
and the methodology used did not support this conclusion. This is a secondary consequence that
need a direct and strong demonstration.
KEYWORDS
Authors did not correctly report all keywords from MeSH Browser. In particular I checked
“Indeterminate liver lesions” and “Chronic liver disease” on MeSH Browser and I did not find
these KWs. This is important, in my personal opinion, in order to increase the traceability of this
paper (and consequently the possibility of the Journal to be cited by Readers and Stakeholders).
I suggest the check of the all KWs.
INTRODUCTION
Although the introduction fits the context of the study, it could be improved. In fact, many
concepts clearly explicated in an exhaustive introduction could help readers to become
passionate about reading the paper and using it as a reference.
First of all, in the background, from line 74 to line 77 the Authors referred to MRI without
specifying the type of contrast media. In fact, there are many diagnostic improvements using Gd-
EOB-DTPA MRI, as reported in other published paper such as J Gastroenterol Hepatol. 2016
Jan;31(1):69-80. doi: 10.1111/jgh.13150. PMID: 26312574. Please, could the Author fix this
point and cite this article? Furthermore, in the background, from line 74 to line 77 the Authors
stated that: “Lesions do not always demonstrate the characteristic radiological features of HCC
(arterial enhancement, and venous phase washout and / or delayed phase washout) [1, 10], or of
any other known liver lesions, and such lesions are therefore classified as indeterminate. These
indeterminate lesions are commonly seen in clinical practice, usually in cirrhotic patients, posing
a diagnostic and prognostic dilemma for clinicians as there are no clear guidelines describing
their significance and management.”. for lesions >1 cm, with no typical imaging findings
(after two or also after only one imaging technique), the guidelines recommend to perform
biopsy. Unfortunately, biopsy is not always performable, and biopsy could produce different
complications. Please, the author could analyze this theme of biopsy, its rate of feasibility and
the need to a noninvasive method to characterize a liver nodule.
MATERIALS & METHODS
It is mandatory to report informations regard the MRI. Which machine? Which contrast media?
Furthermore, it is important to understand if the cases enrolled in this paper as indeterminate
were correctly diagnosed. For example, in the scenario of the response evaluation criteria,
it is well known that the decision on whether a HCC patient is a responder or progressor
after treatment may vary among different radiologists, especially in case of a non-specifically
trained radiologist and, therefore, regardless of the adopted criteria, patients should be
evaluated by experienced radiologists to minimize variability in this critical instance [Eur
Radiol. 2018;28(9):3611-3620. doi:10.1007/s00330-018-5393-3]. Please, could the Authors
report the methodology used (one or more experienced radiologist evaluated MRI?) citing the
aforementioned paper [Eur Radiol. 2018;28(9):3611-3620. doi:10.1007/s00330-018-5393-3].
Moreover, did the authors re-evaluate the imaging of lesions included in the study?
Which version of LI-RADS was used?
Who applied the LI-RADS?
It is important to report why these lesions you enrolled did not undergo BIOPSY.
RESULTS
Results remain clear and well-structured, and no further adjustments are needed.
DISCUSSION
Page 9, line 239: “Our analysis of progression to HCC based on baseline LI-RADS score
showed increasing incidence with increasing score, but our rates were lower than those recently
reported in an American study [16].”. please, the Authors explain the reason for these different
results. In fact, LIRADS has many limitations and no significant improvement in the diagnostic
performance compared with easl in different setting as reported by many published papers
(Liver Int. 2021 Jul 9. doi: 10.1111/liv.15012. Epub ahead of print. PMID: 34242468.  --
Eur J Gastroenterol Hepatol. 2019 Mar;31(3):283-288. doi: 10.1097/MEG.0000000000001269.
PMID: 30234643.).
In my opinion, the authors should emphasize the value of their idea. For example they could
write: “In the era of tailored medicine, such as in other experience like the management of
adverse events with tailored sorafenib dosing that prolongs survival of hepatocellular carcinoma
patients [J Hepatol. 2019;71(6):1175-1183. doi:10.1016/j.jhep.2019.08.015], the results of our
study could help the hepatologists by offering an easy to use tool to identify the patients who
benefit from a tailored surveillance in terms of time and type of imaging (MRI) to use.”.
In the limitation section, it is important to report a limit (if the authors will not improve their
paper with this data): the study did not evaluate if the HCC diagnosed in the study period comes
from an indeterminate nodule. This type of analysis it will be a matter of investigation for a
further study.
TABLES & FIGURES
Tables & Figures are satisfactory, and they correctly match the quality standard of this Journal.
Please review this paper.
user
Title: The fate of indeterminate liver lesions: what proportion are precursors of hepatocellular
carcinoma?
Version: 2 Date: 12 Nov 2021
Reviewer's report:
SPECIFIC COMMENTS
This manuscript is pleasurable and flowing, in general; no major issues are appreciable.
Although language used is appropriate, I (I am not a native English speaker) recommend to
Authors to obtain a certified native speaker with proficiencies in the scientific-medical field to
complete properly this paper (if not jet done). Moreover, I recommend making a further revision
of the manuscript to fix some typing/language errors. For example: “Abstract Background: The
natural history and incidence of hepatocellular carcinoma (HCC) arising from indeterminate
liver lesions is not well characterised.”. evaluate the possibility to change with established.
TITLE
The title is clear and direct. Personally, I believe it could be improved, for example: “The fate
of indeterminate liver lesions: what proportion are precursors of hepatocellular carcinoma? A
retrospective follow-up study”. I suggest removing the last sentence. If the editor agrees, the
authors could consider the change of the title.
ABSTRACT
The abstract is well structured in all its section and, therefore, it properly reflects the main text,
highlighting the most important aspects of this paper. However, some adjustments are needed.
For example: English language and the last sentence in the conclusions: “Our data support a
strategy of enhanced surveillance in patients with indeterminate lesions.”. the aim of the study
and the methodology used did not support this conclusion. This is a secondary consequence that
need a direct and strong demonstration.
KEYWORDS
Authors did not correctly report all keywords from MeSH Browser. In particular I checked
“Indeterminate liver lesions” and “Chronic liver disease” on MeSH Browser and I did not find
these KWs. This is important, in my personal opinion, in order to increase the traceability of this
paper (and consequently the possibility of the Journal to be cited by Readers and Stakeholders).
I suggest the check of the all KWs.
INTRODUCTION
Although the introduction fits the context of the study, it could be improved. In fact, many
concepts clearly explicated in an exhaustive introduction could help readers to become
passionate about reading the paper and using it as a reference.
First of all, in the background, from line 74 to line 77 the Authors referred to MRI without
specifying the type of contrast media. In fact, there are many diagnostic improvements using Gd-
EOB-DTPA MRI, as reported in other published paper such as J Gastroenterol Hepatol. 2016
Jan;31(1):69-80. doi: 10.1111/jgh.13150. PMID: 26312574. Please, could the Author fix this
point and cite this article? Furthermore, in the background, from line 74 to line 77 the Authors
stated that: “Lesions do not always demonstrate the characteristic radiological features of HCC
(arterial enhancement, and venous phase washout and / or delayed phase washout) [1, 10], or of
any other known liver lesions, and such lesions are therefore classified as indeterminate. These
indeterminate lesions are commonly seen in clinical practice, usually in cirrhotic patients, posing
a diagnostic and prognostic dilemma for clinicians as there are no clear guidelines describing
their significance and management.”. for lesions >1 cm, with no typical imaging findings
(after two or also after only one imaging technique), the guidelines recommend to perform
biopsy. Unfortunately, biopsy is not always performable, and biopsy could produce different
complications. Please, the author could analyze this theme of biopsy, its rate of feasibility and
the need to a noninvasive method to characterize a liver nodule.
MATERIALS & METHODS
It is mandatory to report informations regard the MRI. Which machine? Which contrast media?
Furthermore, it is important to understand if the cases enrolled in this paper as indeterminate
were correctly diagnosed. For example, in the scenario of the response evaluation criteria,
it is well known that the decision on whether a HCC patient is a responder or progressor
after treatment may vary among different radiologists, especially in case of a non-specifically
trained radiologist and, therefore, regardless of the adopted criteria, patients should be
evaluated by experienced radiologists to minimize variability in this critical instance [Eur
Radiol. 2018;28(9):3611-3620. doi:10.1007/s00330-018-5393-3]. Please, could the Authors
report the methodology used (one or more experienced radiologist evaluated MRI?) citing the
aforementioned paper [Eur Radiol. 2018;28(9):3611-3620. doi:10.1007/s00330-018-5393-3].
Moreover, did the authors re-evaluate the imaging of lesions included in the study?
Which version of LI-RADS was used?
Who applied the LI-RADS?
It is important to report why these lesions you enrolled did not undergo BIOPSY.
RESULTS
Results remain clear and well-structured, and no further adjustments are needed.
DISCUSSION
Page 9, line 239: “Our analysis of progression to HCC based on baseline LI-RADS score
showed increasing incidence with increasing score, but our rates were lower than those recently
reported in an American study [16].”. please, the Authors explain the reason for these different
results. In fact, LIRADS has many limitations and no significant improvement in the diagnostic
performance compared with easl in different setting as reported by many published papers
(Liver Int. 2021 Jul 9. doi: 10.1111/liv.15012. Epub ahead of print. PMID: 34242468.  --
Eur J Gastroenterol Hepatol. 2019 Mar;31(3):283-288. doi: 10.1097/MEG.0000000000001269.
PMID: 30234643.).
In my opinion, the authors should emphasize the value of their idea. For example they could
write: “In the era of tailored medicine, such as in other experience like the management of
adverse events with tailored sorafenib dosing that prolongs survival of hepatocellular carcinoma
patients [J Hepatol. 2019;71(6):1175-1183. doi:10.1016/j.jhep.2019.08.015], the results of our
study could help the hepatologists by offering an easy to use tool to identify the patients who
benefit from a tailored surveillance in terms of time and type of imaging (MRI) to use.”.
In the limitation section, it is important to report a limit (if the authors will not improve their
paper with this data): the study did not evaluate if the HCC diagnosed in the study period comes
from an indeterminate nodule. This type of analysis it will be a matter of investigation for a
further study.
TABLES & FIGURES
Tables & Figures are satisfactory, and they correctly match the quality standard of this Journal.
assistant