Phosphaturic Mesenchymal Tumors with or without Phosphate Metabolism Derangements
Round 1
Reviewer 1 Report
This paper is a well-written and up-to-date review. Currently, we do not fully understand the exact mechanism of TIO, which is attributed to the heterogeneous nature of the symptoms, as they can both present simultaneously and not at the same time. Furthermore, while there are surgical techniques and medications known to be effective for treatment, they may not always be successful in all cases.
This paper is well organized.
Author Response
We thank the Reviewer for this encouraging comment.
Reviewer 2 Report
This narrative review, authored by multiple specialists of a tertiary care hospital center will describe endocrine, radiological, histological and surgical strategies to manage PMTs.Conclussion: PMTs are rare neoplasms which can present with phosphate metabolism alterations or not. These tumors are often difficult to be identified radiologically and surgery represents the therapeutic option of choice with a curative intent. Cure is less likely when the neoplasm infiltrates the surrounding tissues. In this circumstance, multiple surgeries, the maintenance of medical treatments or both are required in the long term.
The authors perform an excellent review of phosphatin-producing mesenchymal tumors. I would highlight the flowchart for the evaluation of these processes as well as the table of associated biochemical alterations.
Items that could be included: Description of the methodology used to perform the review 20% of these tumors are malignant. The authors could describe their histological origin Indicate the role of PET in the diagnosisAuthor Response
We really thank the Reviewer for these insightful comments. We included a sentence on the methods used to write the Review, which is a narrative Review of the literature (lines 59-63).
We described their histological origin (lines 292-297) and expanded on the role of PET in the diagnosis (lines 222-232). We partially disagree on the malignant nature of these tumors. The overwhelming majority of reported PMTs is benign, although malignancy should always be considered in the differential diagnosis (PMID: 31301876).
Reviewer 3 Report
The manuscript is a review. The quality of the review is good. The important works were cited. In up2date, however, you can find a bit more background information and also some other studies that, in my opinion, should have been mentioned and discussed.
The language an gramma certainly needs careful revision.
Author Response
We appreciated the Reviewer’s comments and suggestions on further background literature to be included. The manuscript was updated in Section 1 and 2.
English language and grammar were revised.
Reviewer 4 Report
In this review the authors highlight that a rare neoplasm known as phosphoturic mesenchymal tumors (PMT) can result in a disease called tumor-induced osteomalacia (TIO), which manifests as physical and neuromuscular symptoms. Finding these tumors is essential to treating the phosphate metabolism issue that results, which frequently leads patients to seek medical attention. Some PMTs can go unnoticed until they grow to a size that causes pain or discomfort. This syndrome is related to FGF-23, a chemical made by various other benign or malignant PMTs. To improve patients' quality of life and implement surgical or interventional treatment plans, the care of PMTs necessitates a multidisciplinary approach including experts from several professions. The authors have discussed and examined the endocrine, radiological, and histological features of these tumors in this review. This review makes a significant contribution to our understanding of this illness and is engaging for readers. The review is written well. Below are my thoughts.
1. In the introduction section please include the statistics of PMT and TIO affected patients worldwide.
2. Line 56, state the median age of presentation as 46 years, with a range from 9 months to 90 years.
3. Line 102, provide a brief overview of the role of alkaline phosphatase and other endocrine indicators in the diagnosis of phosphaturic mesenchymal tumors (PMTs).
4. In the context of PMTs, please explain the link between alkaline phosphatase and osteoblastic activity. Discuss how prolonged 1,25(OH)2 vitamin D suppression can lead to hyperparathyroidism while serum calcium and creatinine levels remain normal.
5. Include studies or experiments that investigate the processes behind the regulation of FGF-23 in PMTs, as well as the conditions under which FGF-23 levels may remain within normal ranges, calling the diagnosis into question.
6. To aid in appropriate differential diagnosis, please propose comparative studies or case series to differentiate the clinical and biochemical aspects of PMTs from genetic rickets.
7. In line 128, the authors can examine the molecular mechanisms behind the synthesis of fibroblast growth factor-23 (FGF-23) in PMTs. Understanding the genetic and molecular processes that contribute to FGF-23 overproduction could lead to new treatment options for TIO.
8. Please compare the diagnostic accuracy and efficiency of various imaging modalities in localizing PMTs (e.g., Technetium bone scintigraphy, Ga-DOTATATE PET/CT, Whole-Body MRI). Conduct a bigger prospective investigation to establish which imaging approach is the most sensitive and specific for early identification and exact localization.
9. Please include examining the radiological properties and patterns of various PMT variants (e.g., PMT-MCT) to help differentiate them from other soft tissue and bone masses.
10. Conduct an investigation to evaluate the value of DWI in PMT diagnosis and characterization. Also examine the relationship between DWI findings and histological characteristics, particularly in distinguishing benign from malignant PMTs.
11. Please include considering the advantages of integrating different imaging techniques, such as PET/CT, MRI, and CT, for a more thorough evaluation of PMTs. Examine how multiple imaging modalities can work together to improve diagnosis accuracy and surgical planning.
12. Please include a paragraph determining potential PMT biomarkers that could aid in early diagnosis, predict disease behavior, and guide treatment decisions.
Author Response
In this review the authors highlight that a rare neoplasm known as phosphoturic mesenchymal tumors (PMT) can result in a disease called tumor-induced osteomalacia (TIO), which manifests as physical and neuromuscular symptoms. Finding these tumors is essential to treating the phosphate metabolism issue that results, which frequently leads patients to seek medical attention. Some PMTs can go unnoticed until they grow to a size that causes pain or discomfort. This syndrome is related to FGF-23, a chemical made by various other benign or malignant PMTs. To improve patients' quality of life and implement surgical or interventional treatment plans, the care of PMTs necessitates a multidisciplinary approach including experts from several professions. The authors have discussed and examined the endocrine, radiological, and histological features of these tumors in this review. This review makes a significant contribution to our understanding of this illness and is engaging for readers. The review is written well. Below are my thoughts.
We really appreciated the Reviewer’s comment.
- In the introduction section please include the statistics of PMT and TIO affected patients worldwide.
Epidemiology of PMT or TIO is lacking because they are extremely rare conditions.
- Line 56, state the median age of presentation as 46 years, with a range from 9 months to 90 years.
The sentence was edited.
- Line 102, provide a brief overview of the role of alkaline phosphatase and other endocrine indicators in the diagnosis of phosphaturic mesenchymal tumors (PMTs).
The role of alk phos as well as that of other endocrine parameters was described in more detail.
- In the context of PMTs, please explain the link between alkaline phosphatase and osteoblastic activity. Discuss how prolonged 1,25(OH)2 vitamin D suppression can lead to hyperparathyroidism while serum calcium and creatinine levels remain normal.
This point was clarified (lines 116-132)
- Include studies or experiments that investigate the processes behind the regulation of FGF-23 in PMTs, as well as the conditions under which FGF-23 levels may remain within normal ranges, calling the diagnosis into question.
We thank the Reviewer for this suggestion. Literature on this topic was added with reference to non-FGF-23 phosphatonins and to molecular genetics of PMTs (lines 143-146 and lines 147-157).
- To aid in appropriate differential diagnosis, please propose comparative studies or case series to differentiate the clinical and biochemical aspects of PMTs from genetic rickets.
The literature was search about this aspect and the manuscript updated accordingly (lines 168-173).
- In line 128, the authors can examine the molecular mechanisms behind the synthesis of fibroblast growth factor-23 (FGF-23) in PMTs. Understanding the genetic and molecular processes that contribute to FGF-23 overproduction could lead to new treatment options for TIO.
We thank the Reviewer for this suggestion. This topic was expanded (lines 143-157)
- Please compare the diagnostic accuracy and efficiency of various imaging modalities in localizing PMTs (e.g., Technetium bone scintigraphy, Ga-DOTATATE PET/CT, Whole-Body MRI). Conduct a bigger prospective investigation to establish which imaging approach is the most sensitive and specific for early identification and exact localization.
Diagnostic accuracy of various imaging modalities was updated, especially regarding Ga-DOTATATE PET-CT and we added the Reviewer’s suggestion in the manuscript (lines 222-232 and 233-235).
- Please include examining the radiological properties and patterns of various PMT variants (e.g., PMT-MCT) to help differentiate them from other soft tissue and bone masses.
This aspect was updated (Paragraph 3).
- Conduct an investigation to evaluate the value of DWI in PMT diagnosis and characterization. Also examine the relationship between DWI findings and histological characteristics, particularly in distinguishing benign from malignant PMTs.
This suggestion was included in the Radiology paragraph (lines 191-194).
- Please include considering the advantages of integrating different imaging techniques, such as PET/CT, MRI, and CT, for a more thorough evaluation of PMTs. Examine how multiple imaging modalities can work together to improve diagnosis accuracy and surgical planning.
We appreciated this comment. This would require a large multicenter study with centralized imaging because TIO is a rare disease. We updated the manuscript with the Reviewer’s suggestion. (lines 236-239)
- Please include a paragraph determining potential PMT biomarkers that could aid in early diagnosis, predict disease behavior, and guide treatment decisions.
TIO is a rare disease and thus far biomarkers are limited. These include bone turnover markers and FGF-23. A correct interpretation of bone turnover markers, 1.25(OH)2 vitamin D and FGF-23 by bone specialists possibly constitute the most predictive biomarkers to describe osteomalacia, tumor presence, and successful tumor removal with surgery or other techniques. (lines 129-132)
