Title: Association between high expression of intratumoral fibroblast activation protein and
survival in patients with intrahepatic cholangiocarcinoma
Version: 1 Date: 09 Jul 2023
Reviewer's report:
Authors focused on the impact of CAFs on the prognosis of iCCA. The study demonstrates that
High intratumoral FAP expression was associated with worse survival. The study lacks novelty
and requires substantial revisions due to multiple areas that need improvement. Additionally,
the clinical implications remain unclear, indicating the need for a major revision.
Major comments:
1) The description of novelty and differentiation from previous reports is insufficient. It is
crucial to clearly articulate how this study differs from prior literature and highlight its novel
contributions.
2) The rationale behind the division of FAP expression into a smaller 25% tile and the use
of median for #-SMA remains unexplained. The current approach appears arbitrary and lacks
justification. Please provide a detailed explanation for the selection of these thresholds for
classification.
3) In cases with high FAP expression, larger tumor sizes and advanced stages were observed,
along with significantly shorter OS and RFS. The speculation regarding FAP's role in creating
a tumor-favorable environment and promoting tumor progression seems plausible. However,
it is crucial to explore the potential reasons why such functionality was not observed in the
peripheral regions where FAP was expressed. Please discuss the possible differences between
FAP-positive cells in the central tumor region and those in the peripheral region.
4) Based on the relationship between immunostaining and prognosis, does the study suggest
functional differences between fibroblasts expressing #-SMA and those expressing FAP? Please
elaborate on the potential roles of fibroblasts that express #-SMA but not FAP, as well as
fibroblasts that express FAP but not #-SMA.
5) The speculation regarding FAP-expressing fibroblasts maintaining cancer stem cells (CSCs)
is intriguing. In the context of anticancer treatment for iCCA, the presence of CSCs in the
central tumor region might be associated with chemotherapy resistance. However, in resected
cases, even if CSCs are present in the central tumor region, their relevance to recurrence seems
less likely because the central region would be completely resected. Instead, the presence of
CSCs in the tumor periphery might be associated with local recurrence. It is important to
provide additional explanations regarding why the abundance of CSCs in the center of resected
specimens is related to recurrence and overall survival.
Minor comments
1) The description regarding the exclusion of patients is confusing, particularly regarding the
reduction in the number of participants from 37 to exclude certain cases. Please revise the
wording to provide clarity.
Title: Association between high expression of intratumoral fibroblast activation protein and
survival in patients with intrahepatic cholangiocarcinoma
Version: 1 Date: 09 Jul 2023
Reviewer's report:
Authors focused on the impact of CAFs on the prognosis of iCCA. The study demonstrates that
High intratumoral FAP expression was associated with worse survival. The study lacks novelty
and requires substantial revisions due to multiple areas that need improvement. Additionally,
the clinical implications remain unclear, indicating the need for a major revision.
Major comments:
1) The description of novelty and differentiation from previous reports is insufficient. It is
crucial to clearly articulate how this study differs from prior literature and highlight its novel
contributions.
2) The rationale behind the division of FAP expression into a smaller 25% tile and the use
of median for #-SMA remains unexplained. The current approach appears arbitrary and lacks
justification. Please provide a detailed explanation for the selection of these thresholds for
classification.
3) In cases with high FAP expression, larger tumor sizes and advanced stages were observed,
along with significantly shorter OS and RFS. The speculation regarding FAP's role in creating
a tumor-favorable environment and promoting tumor progression seems plausible. However,
it is crucial to explore the potential reasons why such functionality was not observed in the
peripheral regions where FAP was expressed. Please discuss the possible differences between
FAP-positive cells in the central tumor region and those in the peripheral region.
4) Based on the relationship between immunostaining and prognosis, does the study suggest
functional differences between fibroblasts expressing #-SMA and those expressing FAP? Please
elaborate on the potential roles of fibroblasts that express #-SMA but not FAP, as well as
fibroblasts that express FAP but not #-SMA.
5) The speculation regarding FAP-expressing fibroblasts maintaining cancer stem cells (CSCs)
is intriguing. In the context of anticancer treatment for iCCA, the presence of CSCs in the
central tumor region might be associated with chemotherapy resistance. However, in resected
cases, even if CSCs are present in the central tumor region, their relevance to recurrence seems
less likely because the central region would be completely resected. Instead, the presence of
CSCs in the tumor periphery might be associated with local recurrence. It is important to
provide additional explanations regarding why the abundance of CSCs in the center of resected
specimens is related to recurrence and overall survival.
Minor comments
1) The description regarding the exclusion of patients is confusing, particularly regarding the
reduction in the number of participants from 37 to exclude certain cases. Please revise the
wording to provide clarity.
Please review this paper.
user
Title: Association between high expression of intratumoral fibroblast activation protein and
survival in patients with intrahepatic cholangiocarcinoma
Version: 1 Date: 09 Jul 2023
Reviewer's report:
Authors focused on the impact of CAFs on the prognosis of iCCA. The study demonstrates that
High intratumoral FAP expression was associated with worse survival. The study lacks novelty
and requires substantial revisions due to multiple areas that need improvement. Additionally,
the clinical implications remain unclear, indicating the need for a major revision.
Major comments:
1) The description of novelty and differentiation from previous reports is insufficient. It is
crucial to clearly articulate how this study differs from prior literature and highlight its novel
contributions.
2) The rationale behind the division of FAP expression into a smaller 25% tile and the use
of median for #-SMA remains unexplained. The current approach appears arbitrary and lacks
justification. Please provide a detailed explanation for the selection of these thresholds for
classification.
3) In cases with high FAP expression, larger tumor sizes and advanced stages were observed,
along with significantly shorter OS and RFS. The speculation regarding FAP's role in creating
a tumor-favorable environment and promoting tumor progression seems plausible. However,
it is crucial to explore the potential reasons why such functionality was not observed in the
peripheral regions where FAP was expressed. Please discuss the possible differences between
FAP-positive cells in the central tumor region and those in the peripheral region.
4) Based on the relationship between immunostaining and prognosis, does the study suggest
functional differences between fibroblasts expressing #-SMA and those expressing FAP? Please
elaborate on the potential roles of fibroblasts that express #-SMA but not FAP, as well as
fibroblasts that express FAP but not #-SMA.
5) The speculation regarding FAP-expressing fibroblasts maintaining cancer stem cells (CSCs)
is intriguing. In the context of anticancer treatment for iCCA, the presence of CSCs in the
central tumor region might be associated with chemotherapy resistance. However, in resected
cases, even if CSCs are present in the central tumor region, their relevance to recurrence seems
less likely because the central region would be completely resected. Instead, the presence of
CSCs in the tumor periphery might be associated with local recurrence. It is important to
provide additional explanations regarding why the abundance of CSCs in the center of resected
specimens is related to recurrence and overall survival.
Minor comments
1) The description regarding the exclusion of patients is confusing, particularly regarding the
reduction in the number of participants from 37 to exclude certain cases. Please revise the
wording to provide clarity.
assistant