Liver and Vascular Involvement in Philadelphia-Negative Chronic Myeloproliferative Neoplasms—A Narrative Review
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe review article by Romeo G Mihăilă et al entitled ‘Liver and Vascular Involvement in Philadelphia-negative Chronic Myeloproliferative Neoplasms - A Narrative Review’ focuses on liver extramedullary hematopoiesis liked with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs). The review is extensive and elaborate with clear figures and tables. However, the following minor changes can be included to further improve the article.
- Overall, the abstract or conclusion can be too elaborate for readers. Sorting the information sequentially may help to gain reader interest.
- In lines 70-76, the advantages of Splenic transient elastography, MRI, and PET/CT scan are mentioned. It would be beneficial to compare and contrast between these methods with their advantages or limitations.
- In line 796, the need for Hydroxycarbamidum in large clinical trial is highlighted without any suggestion for mitigating its side effects. Any study on resolving its side effects can be discussed along with clinical trial.
Author Response
Comment 1: Overall, the abstract or conclusion can be too elaborate for readers. Sorting the information sequentially may help to gain reader interest.
Response:
Thank you for your valuable feedback. We agree that clarity and conciseness are essential, especially in the abstract and conclusion. Accordingly, we have revised both sections to present the information in a more sequential and streamlined manner, improving readability and maintaining the logical flow. We believe this adjustment will help readers better grasp the key points of the study.
Comment 2: In lines 70-76, the advantages of Splenic transient elastography, MRI, and PET/CT scan are mentioned. It would be beneficial to compare and contrast between these methods with their advantages or limitations.
Response: Thank you for your insightful comment. We agree that a comparative discussion of these imaging modalities would enhance the clarity and depth of the manuscript. Accordingly, we have added a comparative paragraph outlining the respective advantages and limitations of splenic transient elastography, MRI, and PET/CT, as follows:
While splenic elastography is rapid, non-invasive, and cost-effective, it may be limited by technical factors such as body habitus or ascites. MRI offers detailed anatomical and fat quantification information, but it is more expensive and less widely available. PET/CT provides functional imaging that can detect metabolic and proliferative activity, but it involves radiation exposure and may lack specificity in distinguishing reactive from clonal processes.
Comment 3: In line 796, the need for Hydroxycarbamide in large clinical trial is highlighted without any suggestion for mitigating its side effects. Any study on resolving its side effects can be discussed along with clinical trial.
Response: Thank you for this valuable observation. We agree that including data on strategies to mitigate Hydroxycarbamide’s side effects would provide a more comprehensive view. We have revised the text to address your concern.
Reviewer 2 Report
Comments and Suggestions for AuthorsIn this review by Romeo G Mihaila et al., the authors aim to analyze the connections between Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) and the liver.
They introduced the most common forms or MPNs along with their characteristics both at clinical and molecular level, mainly describing the involvement of JAK/STAT pathways and the point mutation (V617F) in the Janus kinase 2 (JAK2) gene (JAK2V617F).
Moreover, they describe the overall clinical aspects of MPNs, describing the effects not only on the liver, but also on spleen stiffness, bone marrow fibrosis, upper gastrointestinal bleeding and others.
They finally describe the possible therapeutic interventions with possible outcomes and side effects.
This review is well done; it contains a lot of information from both a clinical and molecular point of view. The figures are nice.
Since the information contained is so much, it often goes from clinical to molecular information and back to clinical again, making it difficult to understand for example which biomarkers are useful for or that can help in the diagnosis.
It would be nice to have a table summarizing the clinical parameters and/or possible molecular biomarkers to be considered for the diagnosis.
In paragraph 2, Liver and myelofibrosis, lines 110-114: can they mention some/the most relevant pro-inflammatory genes they are referring to? Additionally, in lines 119-122 they describe the miRNAs as “potential targets for therapeutic developments in fibrotic disorders”. Can they make some examples of these miRNAs involved in fibrotic disorders?
Please, separate the main text from the titles and legends in figure 1 and 2 as well as the title and the legends of tables 1 and 2 (lines150, 153, 286, 472, 475, 480, 482).
Please double check the manuscripts for writing form, corrections and typos. E.g:
- Lines 428-429: they inserted the acronym TIPS and its description “transjugular intrahepatic portosystemic shunt”, but TIPS was used already in lines 391, 392 abd 395 without description.
- Paragraphs 4 and 5 have the same title
- Paragraph 4, line 202: “The median liver and spleen SS…” SS was described at the beginning (line 197) as spleen stiffness
- Abstract, lines 15-17: please choose whether use present or past
- In paragraph 2, lines 96-97: “chronic inflammation and disease progression with the migration of hematopoietic stem cells from the bone marrow including in the liver and spleen” is including intended to be used?
Author Response
Comment: Since the information contained is so much, it often goes from clinical to molecular information and back to clinical again, making it difficult to understand for example which biomarkers are useful for or that can help in the diagnosis.
It would be nice to have a table summarizing the clinical parameters and/or possible molecular biomarkers to be considered for the diagnosis.
Response: Thank you for this constructive suggestion. We agree that a summary table would greatly enhance clarity and assist readers in navigating the complex information. We have therefore added a table summarizing key clinical parameters and molecular biomarkers relevant for the diagnosis of myeloproliferative neoplasms and related liver involvement.
Comment: In paragraph 2, Liver and myelofibrosis, lines 110-114: can they mention some/the most relevant pro-inflammatory genes they are referring to?
Response: Thank you for your valuable comment. We have now clarified the pro-inflammatory genes referenced in this section.
Comment: Additionally, in lines 119-122 they describe the miRNAs as “potential targets for therapeutic developments in fibrotic disorders”. Can they make some examples of these miRNAs involved in fibrotic disorders?
Response: Thank you for your helpful suggestion. In response, we have added representative examples of miRNAs implicated in fibrotic disorders to enhance the specificity of this statement.
Comment: Please, separate the main text from the titles and legends in figure 1 and 2 as well as the title and the legends of tables 1 and 2 (lines150, 153, 286, 472, 475, 480, 482).
Response: Thank you for the suggestion. We have now separated the main text from the titles and legends of Figure 1 and Figure 2, as well as those of Tables 1 and 2, at the specified lines (150, 153, 286, 472, 475, 480, and 482), to improve clarity and consistency in formatting.
Comment: Please double check the manuscripts for writing form, corrections and typos. E.g:
Lines 428-429: they inserted the acronym TIPS and its description “transjugular intrahepatic portosystemic shunt”, but TIPS was used already in lines 391, 392 abd 395 without description.
Response: Thank you for pointing this out. We have revised the manuscript to ensure that the acronym TIPS (transjugular intrahepatic portosystemic shunt) is introduced appropriately upon its first mention in the text (line 391), and we have removed the redundant explanation at lines 428–429 to maintain consistency and avoid repetition. The manuscript has also been re-checked for form, spelling, and typographical errors, with necessary corrections applied throughout.
Comment: Paragraphs 4 and 5 have the same title
Response: Thank you for your observation. We have corrected the duplicated title. Paragraph 5 now bears the appropriate heading "Extramedullary Hematopoiesis", to reflect its content accurately and maintain structural clarity throughout the manuscript.
Comment: Paragraph 4, line 202: “The median liver and spleen SS…” SS was described at the beginning (line 197) as spleen stiffness
Response: You're correct. Since “SS” was already defined as spleen stiffness at line 197, the phrase “liver and spleen SS” in line 202 is inconsistent and potentially confusing.
Here is a corrected version of that sentence:
“The median LS and SS values were higher in patients with higher versus lower grades of bone marrow fibrosis (5.2 vs. 6.65 kPa for liver stiffness, and 27.2 vs. 37.9 kPa for spleen stiffness) [30].”
Comment: Abstract, lines 15-17: please choose whether use present or past
Response: Thank you for your observation. We have revised the abstract to consistently use the present tense.
Comment: In paragraph 2, lines 96-97: “chronic inflammation and disease progression with the migration of hematopoietic stem cells from the bone marrow including in the liver and spleen” is including intended to be used?
Response: Certainly! Here's a revised version of the sentence without using "including":
Original:
“…chronic inflammation and disease progression with the migration of hematopoietic stem cells from the bone marrow including in the liver and spleen.”
Reformulated:
“…chronic inflammation and disease progression, characterized by the migration of hematopoietic stem cells from the bone marrow to extramedullary sites such as the liver and spleen.”
