Title: Risks and Benefits of TIPS in HCC and Other Liver Malignancies: a literature review
Version: 0 Date: 08 Aug 2023
Reviewer:  Theresa Bucsics
Reviewer's report:
First of all, I want to congratulate the authors Fichtl, Seufferlein and Zizer on their excellently
written review and the selection of this clinically highly relevant topic.  Indeed, the clinical
relevance, feasibility, safety, and effectiveness vs. risks of TIPS in HCC is something that is
discussed in interdisciplinary boards on a regular basis.
The manuscript is concise and well structured.
However, there are some issues that need to be revised, and some claims and statements  that I
do not agree with and that are not backed up by the literature that is referenced.
MAJOR:
- For a (literary)  review, the authors should not only cite the literature via footnote, but  a) read
thoroughly and critically evaluate the references and b) present the data of the reviewed article(s)
in a way that allows for statistical  interpretation:  Hence, I kindly ask the authors to present the
numbers/data with confidence intervals (e.g. standard deviation, IQR, ranges, 95% CI...) and
ideally p-values, when avaiable, when comparing groups or cohorts. Without this information,
it is difficult to interpret the data.
Else, the authors should at least mention whether the reported differences between groups/
cohorts attained statistical significance or not.
Similarly, the authors should be precise when reporting data.
i) For instance, page 6, lines 66ff, it is unclear which of the two studies the numbers and
percentages  are referring to (or did the authors calculate pooled numbers?), and the survival
times are hard to interpret without knowing the ranges of measurement.
ii) Page 7, lines 89 - 95: Are the differences between groups statistically significant? What are
the p values? With such low patient numbers, the percentages alone are impossible to interpret.
iii) On page 8, line 120, the authors wrote "... and indicated a good clinical response". What
does "good clinical response" mean - fewer thoracocenteses, lower doses of diuretics required,
no need for any further treatment at all, better quality of life? Could the authors please provide
context?
- As for point a):
i)  Page 3, lines 27-28: The authors wrote "Hepatocellular carcinoma (HCC) is the leading cause
of death in patients with liver cirrhosis."
I’m not convinced that this is true, as most patients with cirrhosis do NOT develop
HCC (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9579565/), while ACLF including renal
failure, (gastrointestinal) bleedings and sepsis are very common causes for death in cirrhosis.
(This also explains why the findings on page 6, lines 69- 72,  are  rather unsurprising than
"interesting").
I  kindly ask the reviewers to provide a source for this claim, as the referenced study is
a review by itself and not a primary source. The study that was referenced in the review
discussed HCC *becoming* a major cause of death, but attributed only 18.4% of deaths
in patients with initially compensated viral cirrhosis to HCC: https://pubmed-ncbi-nlm-nih-
gov.ez.srv.meduniwien.ac.at/25678021/ ).
ii)  Page 8, lines 130-131: The authors wrote "(...) not all studies on TIPS for PVTT in HCC
confirmed PVTT via biopsy" (and cite only one source). If vascularization is present in the portal
vein thrombus in ultrasound/CT/MRI scan, biopsy is not necessarily required for diagnosis, so I
am not sure I understand the argument. If it is recommended by current guidlines/SOP, I kindly
ask the authors to provide the appropriate source.
iii)  Topic HE after TIPS (page 10): What grade of HE are the authors referring to? Any grade,
or overt HE, or HE II-IV according to West Haven criteria? Unfortunately, there is a large
heterogeneity in HE reporting between studies, especially for TIPS patients, which renders
comparability between studies almost impossible.
iv) Page 11, lines 198-199: "(...) carrying out TACE before TIPS implantation should be
considered":
Why? Does sequential treatment lower the risk of liver failure due to TIPS + TACE as compared
to combined treatment or TIPS before TACE? I cannot draw this conclusion from the paragraphs
and data that the authors provided. This sentence is also  somewhat contradictory to page 12,
lines 208-209: "By relieving the symptoms of PH, TIPS renders the patients eligible for further
HCC treatment." What is the main conclusion/recommendation on the sequence of TIPS/TACE/
other locoregional therapies in patients with CSPH and HCC within Milan?
v) Page 12, lines 214-216: The reference (61) is a retrospective study (by reviewing data from
a database), not a review.
vi) page 12, lines 217 - 222: In the referenced study (62), patients were not transplanted DUE TO
HCC within Milan – this would render the whole intent of the study to identify the prevalence
of occult HCC pointless – but patients with histological proof of HCC in explant livers were
retrospectively assessed for TIPS status, and a higher fraction of patients with occult HCC that
was not previously diagnosed were identified in those with TIPS vs in those without TIPS.
Consecutively, lines 221-222: I believe the authors mean «with 80%, patients with TIPS were
more likely to present with occult HCC»
vii): page 13, lines 237-238: The finding of "1% rate of lung metastases after TIPS placement"
and also table 2 are impossible to interpret without knowing the overall prevalence/rate of lung
metastases in (metastatic) HCC. I kindly ask the authors to provide this information.
viii): page 13, lines 238 - 239: "(...) there is no standardized periprocedural screening for
lung metastases": The authors should verify, by review of current national and international
guidelines, whether thoracic/chest CT scans (in combination with abdominal CT and/or MRI
scans) are truly not recommended or even SOP for HCC staging/re-staging assessments. As far
as I know, exclusion of metastatic disease is required in order to stage the patient according to
the BCLC criteria, on which the most recent treatment algorithm for HCC is based on.
ix) Table 3: Wallace et al., HCC: N=13, CCC=1. Considering that the table is titled "case series
of patients with liver malignancies other than HCC who received TIPS", could the authors please
state how many of these patients suffered from cirrhosis, or were all HCC cases  in non-cirrhotic
livers? If a significant proportion had cirrhosis, I would exclude the study from this table as it
comprises an entirely different cohort.
MINOR:
- Page 3, line 21: "TIPS is crucial for managing CSPH (..."): effective/established yes, but not
yet crucial I am afraid, as only a fraction of patients with CSPH actually qualify for TIPS. I
would rather regard NSBB (and diuretics/EBL) as "crucial".
- Page 7, line 97: Although the authors report verbatim from the original study the threshold for
MELD of ">= 15.5", there is no decimal for MELD, as MELD is always rounded down.
- Page 11, lines 193-194: "(...) impaired treatment response to TACE in patients undergoing
TIPS placement" - undergoing TIPS placement, or in patients with (previously implanted) TIPS?
- Page 14, line 247: "(...) but three of these patients did not have their shunt created due to the
tumour". This sentence is unclear; why would patients receive TIPS DUE to the tumour? HCC
is not an indication for TIPS – complications of CSPH are.
- page 15, lines 268-269: The only p-value presented is reporting a statistical decrease in PPG
after TIPS, although it is known as a fact at this point that TIPS is very effective in decreasing
portal pressure...
- Table 3: The 67% rate of post-TIPS HE in patients with non-HCC liver malignancies by Shreve
et al. is astoundingly high. In my experience, HE is rather low in patients without primary hepatic
diseases.
Title: Risks and Benefits of TIPS in HCC and Other Liver Malignancies: a literature review
Version: 0 Date: 08 Aug 2023
Reviewer:  Theresa Bucsics
Reviewer's report:
First of all, I want to congratulate the authors Fichtl, Seufferlein and Zizer on their excellently
written review and the selection of this clinically highly relevant topic.  Indeed, the clinical
relevance, feasibility, safety, and effectiveness vs. risks of TIPS in HCC is something that is
discussed in interdisciplinary boards on a regular basis.
The manuscript is concise and well structured.
However, there are some issues that need to be revised, and some claims and statements  that I
do not agree with and that are not backed up by the literature that is referenced.
MAJOR:
- For a (literary)  review, the authors should not only cite the literature via footnote, but  a) read
thoroughly and critically evaluate the references and b) present the data of the reviewed article(s)
in a way that allows for statistical  interpretation:  Hence, I kindly ask the authors to present the
numbers/data with confidence intervals (e.g. standard deviation, IQR, ranges, 95% CI...) and
ideally p-values, when avaiable, when comparing groups or cohorts. Without this information,
it is difficult to interpret the data.
Else, the authors should at least mention whether the reported differences between groups/
cohorts attained statistical significance or not.
Similarly, the authors should be precise when reporting data.
i) For instance, page 6, lines 66ff, it is unclear which of the two studies the numbers and
percentages  are referring to (or did the authors calculate pooled numbers?), and the survival
times are hard to interpret without knowing the ranges of measurement.
ii) Page 7, lines 89 - 95: Are the differences between groups statistically significant? What are
the p values? With such low patient numbers, the percentages alone are impossible to interpret.
iii) On page 8, line 120, the authors wrote "... and indicated a good clinical response". What
does "good clinical response" mean - fewer thoracocenteses, lower doses of diuretics required,
no need for any further treatment at all, better quality of life? Could the authors please provide
context?
- As for point a):
i)  Page 3, lines 27-28: The authors wrote "Hepatocellular carcinoma (HCC) is the leading cause
of death in patients with liver cirrhosis."
I’m not convinced that this is true, as most patients with cirrhosis do NOT develop
HCC (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9579565/), while ACLF including renal
failure, (gastrointestinal) bleedings and sepsis are very common causes for death in cirrhosis.
(This also explains why the findings on page 6, lines 69- 72,  are  rather unsurprising than
"interesting").
I  kindly ask the reviewers to provide a source for this claim, as the referenced study is
a review by itself and not a primary source. The study that was referenced in the review
discussed HCC *becoming* a major cause of death, but attributed only 18.4% of deaths
in patients with initially compensated viral cirrhosis to HCC: https://pubmed-ncbi-nlm-nih-
gov.ez.srv.meduniwien.ac.at/25678021/ ).
ii)  Page 8, lines 130-131: The authors wrote "(...) not all studies on TIPS for PVTT in HCC
confirmed PVTT via biopsy" (and cite only one source). If vascularization is present in the portal
vein thrombus in ultrasound/CT/MRI scan, biopsy is not necessarily required for diagnosis, so I
am not sure I understand the argument. If it is recommended by current guidlines/SOP, I kindly
ask the authors to provide the appropriate source.
iii)  Topic HE after TIPS (page 10): What grade of HE are the authors referring to? Any grade,
or overt HE, or HE II-IV according to West Haven criteria? Unfortunately, there is a large
heterogeneity in HE reporting between studies, especially for TIPS patients, which renders
comparability between studies almost impossible.
iv) Page 11, lines 198-199: "(...) carrying out TACE before TIPS implantation should be
considered":
Why? Does sequential treatment lower the risk of liver failure due to TIPS + TACE as compared
to combined treatment or TIPS before TACE? I cannot draw this conclusion from the paragraphs
and data that the authors provided. This sentence is also  somewhat contradictory to page 12,
lines 208-209: "By relieving the symptoms of PH, TIPS renders the patients eligible for further
HCC treatment." What is the main conclusion/recommendation on the sequence of TIPS/TACE/
other locoregional therapies in patients with CSPH and HCC within Milan?
v) Page 12, lines 214-216: The reference (61) is a retrospective study (by reviewing data from
a database), not a review.
vi) page 12, lines 217 - 222: In the referenced study (62), patients were not transplanted DUE TO
HCC within Milan – this would render the whole intent of the study to identify the prevalence
of occult HCC pointless – but patients with histological proof of HCC in explant livers were
retrospectively assessed for TIPS status, and a higher fraction of patients with occult HCC that
was not previously diagnosed were identified in those with TIPS vs in those without TIPS.
Consecutively, lines 221-222: I believe the authors mean «with 80%, patients with TIPS were
more likely to present with occult HCC»
vii): page 13, lines 237-238: The finding of "1% rate of lung metastases after TIPS placement"
and also table 2 are impossible to interpret without knowing the overall prevalence/rate of lung
metastases in (metastatic) HCC. I kindly ask the authors to provide this information.
viii): page 13, lines 238 - 239: "(...) there is no standardized periprocedural screening for
lung metastases": The authors should verify, by review of current national and international
guidelines, whether thoracic/chest CT scans (in combination with abdominal CT and/or MRI
scans) are truly not recommended or even SOP for HCC staging/re-staging assessments. As far
as I know, exclusion of metastatic disease is required in order to stage the patient according to
the BCLC criteria, on which the most recent treatment algorithm for HCC is based on.
ix) Table 3: Wallace et al., HCC: N=13, CCC=1. Considering that the table is titled "case series
of patients with liver malignancies other than HCC who received TIPS", could the authors please
state how many of these patients suffered from cirrhosis, or were all HCC cases  in non-cirrhotic
livers? If a significant proportion had cirrhosis, I would exclude the study from this table as it
comprises an entirely different cohort.
MINOR:
- Page 3, line 21: "TIPS is crucial for managing CSPH (..."): effective/established yes, but not
yet crucial I am afraid, as only a fraction of patients with CSPH actually qualify for TIPS. I
would rather regard NSBB (and diuretics/EBL) as "crucial".
- Page 7, line 97: Although the authors report verbatim from the original study the threshold for
MELD of ">= 15.5", there is no decimal for MELD, as MELD is always rounded down.
- Page 11, lines 193-194: "(...) impaired treatment response to TACE in patients undergoing
TIPS placement" - undergoing TIPS placement, or in patients with (previously implanted) TIPS?
- Page 14, line 247: "(...) but three of these patients did not have their shunt created due to the
tumour". This sentence is unclear; why would patients receive TIPS DUE to the tumour? HCC
is not an indication for TIPS – complications of CSPH are.
- page 15, lines 268-269: The only p-value presented is reporting a statistical decrease in PPG
after TIPS, although it is known as a fact at this point that TIPS is very effective in decreasing
portal pressure...
- Table 3: The 67% rate of post-TIPS HE in patients with non-HCC liver malignancies by Shreve
et al. is astoundingly high. In my experience, HE is rather low in patients without primary hepatic
diseases.
Please review this paper.
user
Title: Risks and Benefits of TIPS in HCC and Other Liver Malignancies: a literature review
Version: 0 Date: 08 Aug 2023
Reviewer:  Theresa Bucsics
Reviewer's report:
First of all, I want to congratulate the authors Fichtl, Seufferlein and Zizer on their excellently
written review and the selection of this clinically highly relevant topic.  Indeed, the clinical
relevance, feasibility, safety, and effectiveness vs. risks of TIPS in HCC is something that is
discussed in interdisciplinary boards on a regular basis.
The manuscript is concise and well structured.
However, there are some issues that need to be revised, and some claims and statements  that I
do not agree with and that are not backed up by the literature that is referenced.
MAJOR:
- For a (literary)  review, the authors should not only cite the literature via footnote, but  a) read
thoroughly and critically evaluate the references and b) present the data of the reviewed article(s)
in a way that allows for statistical  interpretation:  Hence, I kindly ask the authors to present the
numbers/data with confidence intervals (e.g. standard deviation, IQR, ranges, 95% CI...) and
ideally p-values, when avaiable, when comparing groups or cohorts. Without this information,
it is difficult to interpret the data.
Else, the authors should at least mention whether the reported differences between groups/
cohorts attained statistical significance or not.
Similarly, the authors should be precise when reporting data.
i) For instance, page 6, lines 66ff, it is unclear which of the two studies the numbers and
percentages  are referring to (or did the authors calculate pooled numbers?), and the survival
times are hard to interpret without knowing the ranges of measurement.
ii) Page 7, lines 89 - 95: Are the differences between groups statistically significant? What are
the p values? With such low patient numbers, the percentages alone are impossible to interpret.
iii) On page 8, line 120, the authors wrote "... and indicated a good clinical response". What
does "good clinical response" mean - fewer thoracocenteses, lower doses of diuretics required,
no need for any further treatment at all, better quality of life? Could the authors please provide
context?
- As for point a):
i)  Page 3, lines 27-28: The authors wrote "Hepatocellular carcinoma (HCC) is the leading cause
of death in patients with liver cirrhosis."
I’m not convinced that this is true, as most patients with cirrhosis do NOT develop
HCC (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9579565/), while ACLF including renal
failure, (gastrointestinal) bleedings and sepsis are very common causes for death in cirrhosis.
(This also explains why the findings on page 6, lines 69- 72,  are  rather unsurprising than
"interesting").
I  kindly ask the reviewers to provide a source for this claim, as the referenced study is
a review by itself and not a primary source. The study that was referenced in the review
discussed HCC *becoming* a major cause of death, but attributed only 18.4% of deaths
in patients with initially compensated viral cirrhosis to HCC: https://pubmed-ncbi-nlm-nih-
gov.ez.srv.meduniwien.ac.at/25678021/ ).
ii)  Page 8, lines 130-131: The authors wrote "(...) not all studies on TIPS for PVTT in HCC
confirmed PVTT via biopsy" (and cite only one source). If vascularization is present in the portal
vein thrombus in ultrasound/CT/MRI scan, biopsy is not necessarily required for diagnosis, so I
am not sure I understand the argument. If it is recommended by current guidlines/SOP, I kindly
ask the authors to provide the appropriate source.
iii)  Topic HE after TIPS (page 10): What grade of HE are the authors referring to? Any grade,
or overt HE, or HE II-IV according to West Haven criteria? Unfortunately, there is a large
heterogeneity in HE reporting between studies, especially for TIPS patients, which renders
comparability between studies almost impossible.
iv) Page 11, lines 198-199: "(...) carrying out TACE before TIPS implantation should be
considered":
Why? Does sequential treatment lower the risk of liver failure due to TIPS + TACE as compared
to combined treatment or TIPS before TACE? I cannot draw this conclusion from the paragraphs
and data that the authors provided. This sentence is also  somewhat contradictory to page 12,
lines 208-209: "By relieving the symptoms of PH, TIPS renders the patients eligible for further
HCC treatment." What is the main conclusion/recommendation on the sequence of TIPS/TACE/
other locoregional therapies in patients with CSPH and HCC within Milan?
v) Page 12, lines 214-216: The reference (61) is a retrospective study (by reviewing data from
a database), not a review.
vi) page 12, lines 217 - 222: In the referenced study (62), patients were not transplanted DUE TO
HCC within Milan – this would render the whole intent of the study to identify the prevalence
of occult HCC pointless – but patients with histological proof of HCC in explant livers were
retrospectively assessed for TIPS status, and a higher fraction of patients with occult HCC that
was not previously diagnosed were identified in those with TIPS vs in those without TIPS.
Consecutively, lines 221-222: I believe the authors mean «with 80%, patients with TIPS were
more likely to present with occult HCC»
vii): page 13, lines 237-238: The finding of "1% rate of lung metastases after TIPS placement"
and also table 2 are impossible to interpret without knowing the overall prevalence/rate of lung
metastases in (metastatic) HCC. I kindly ask the authors to provide this information.
viii): page 13, lines 238 - 239: "(...) there is no standardized periprocedural screening for
lung metastases": The authors should verify, by review of current national and international
guidelines, whether thoracic/chest CT scans (in combination with abdominal CT and/or MRI
scans) are truly not recommended or even SOP for HCC staging/re-staging assessments. As far
as I know, exclusion of metastatic disease is required in order to stage the patient according to
the BCLC criteria, on which the most recent treatment algorithm for HCC is based on.
ix) Table 3: Wallace et al., HCC: N=13, CCC=1. Considering that the table is titled "case series
of patients with liver malignancies other than HCC who received TIPS", could the authors please
state how many of these patients suffered from cirrhosis, or were all HCC cases  in non-cirrhotic
livers? If a significant proportion had cirrhosis, I would exclude the study from this table as it
comprises an entirely different cohort.
MINOR:
- Page 3, line 21: "TIPS is crucial for managing CSPH (..."): effective/established yes, but not
yet crucial I am afraid, as only a fraction of patients with CSPH actually qualify for TIPS. I
would rather regard NSBB (and diuretics/EBL) as "crucial".
- Page 7, line 97: Although the authors report verbatim from the original study the threshold for
MELD of ">= 15.5", there is no decimal for MELD, as MELD is always rounded down.
- Page 11, lines 193-194: "(...) impaired treatment response to TACE in patients undergoing
TIPS placement" - undergoing TIPS placement, or in patients with (previously implanted) TIPS?
- Page 14, line 247: "(...) but three of these patients did not have their shunt created due to the
tumour". This sentence is unclear; why would patients receive TIPS DUE to the tumour? HCC
is not an indication for TIPS – complications of CSPH are.
- page 15, lines 268-269: The only p-value presented is reporting a statistical decrease in PPG
after TIPS, although it is known as a fact at this point that TIPS is very effective in decreasing
portal pressure...
- Table 3: The 67% rate of post-TIPS HE in patients with non-HCC liver malignancies by Shreve
et al. is astoundingly high. In my experience, HE is rather low in patients without primary hepatic
diseases.
assistant