Detection of the Lassa Virus in a Group of Odontogenic Bone Tumor Tissues
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
Interesting article.
I would just suggest Authors to discuss recent epidemiology of odontogenic fibrous-bone tumors. To this aim, Authors could also cite the recent relevant literature, e.g.:
The epidemiology and management of ameloblastomas: A European multicenter study. J Craniomaxillofac Surg. 2021 Dec;49(12):1107-1112.
Author Response
Reviewer 1
Interesting article.
I would just suggest Authors to discuss recent epidemiology of odontogenic fibrous-bone tumors. To this aim, Authors could also cite the recent relevant literature, e.g.:
The epidemiology and management of ameloblastomas: A European multicenter study. J Craniomaxillofac Surg. 2021 Dec;49(12):1107-1112.
Response: We thank the positive comment of the reviewer and in agreement, we have revised the text adding new references and commenting on the suggested article, new ref. 4 in the revised version.
Reviewer 2 Report
Comments and Suggestions for Authors
The article "Detection of Lassa virus in a group of odontogenic fibrous-bone tumors tissues"is very interesting.
I have some comments to make:
- It is not very correct to comment on unpublished observations (line 304-309)
- In line 315, to use the word tumor better than cancer.
- Initially, did the authors consider treating with antiviral drugs to try to reduce the tumor?
-The contribution towards pathogenesis or comorbidity of Lassa virus and OT is a strong point in their possible association in humans. The weak point is a series of few cases.
-This is an observational study without a control group. It would be interesting to document the comparison of cases without Lassa virus to determine factors such as the degree of growth or recurrence.
-The methodological design is adequate in what is required for the presentation of the cases, through photographs and histology.
-Table 3 may not be necessary
Author Response
Reviewer 2
The article "Detection of Lassa virus in a group of odontogenic fibrous-bone tumors tissues is very interesting.
I have some comments to make:
- It is not very correct to comment on unpublished observations (line 304-309)
Response: Thanks so much for the comment. We have removed this observation from the text. In fact, we are collecting more data to make a publication.- In line 315, to use the word tumor better than cancer.
Response: We amended.- Initially, did the authors consider treating with antiviral drugs to try to reduce the tumor?
Response: We thank the reviewer for this thoughtful comment. Unfortunately, the patients who arrive in Kinshasa from all the neighboring villages for the operation already have a very large tumor mass as visible in Fig. 2 and the surgery is the only option. We thought about administering the antiviral Ribavirin after the operation to contain relapses, since it seems effective only in the very early stages of the infectious process, although it is not specific to LASV. However, the lack of a public health system and the high cost of the antiviral have made this therapeutic strategy impossible. One of our young patients belonging to this cohort died at the seventh relapse, also positive for LASV.-The contribution towards pathogenesis or comorbidity of Lassa virus and OT is a strong point in their possible association in humans. The weak point is a series of few cases.
-This is an observational study without a control group. It would be interesting to document the comparison of cases without Lassa virus to determine factors such as the degree of growth or recurrence.
Response: We thank the reviewer's very true comment. In the revised text we have better clarified that this is an observational study and which will need further investigation in the future.
We well know that the number of patients is small and in fact we have classified the results as both an observational study and a case report. To respond to the comments raised by the reviewer, we are organizing in collaboration with the research group of Prof. Paolo Bonfanti, infectious disease specialist at the University of Milan “La Bicocca”, Italy, with prof. Adrian Kamulegeya, Prof. of Maxillo-Facial & Oral Surgeon at Makerere University, Kampala and with Uganda Viral Research Institute, a two-arm study, a control group and a group of patients with OT, approximately 50-80 patients per group according the power calculation carried out. It will also be our intention to carry out sequencing to genotype LASV.
-The methodological design is adequate in what is required for the presentation of the cases, through photographs and histology.
Response: Many thanks for the positive comment.-Table 3 may not be necessary
Response: Accordingly, we have removed this table and corrected the number of the other tables.
Reviewer 3 Report
Comments and Suggestions for Authors
Thank you for your paper. The study you perform is a novelty in the field of such lesions. As so, it is surely of note. I suggest only to better higllight that the present study is a preliminary or investigative type of study in the abstract, discussion and conclusion, also suggestiong to the readers or other researcher to findo out more additive data about such possible association.
Thank you again for your well conducted study.
Author Response
Reviewer 3
Thank you for your paper.
The study you perform is a novelty in the field of such lesions.
Response: We thank the reviewer for the positive comment.
As so, it is surely of note. I suggest only to better highlight that the present study is a preliminary or investigative type of study in the abstract, discussion and conclusion, also suggesting to the readers or other researcher to find out more additive data about such possible association.
Response: According to these comments, we added some sentences in all sections indicated by the reviewer.
Thank you again for your well conducted study.
Response: Many thanks for the suggestions and the positive comments.
Reviewer 4 Report
Comments and Suggestions for Authors
The manuscript authored by De Feo M. et al. is well done.
Summary:
In their study, the authors elucidate the association between the Lassa virus and odontogenic tumors, primarily focusing on ossifying fibroma. They present findings from nine cases, all of which underwent molecular studies to detect the presence of the Lassa virus.
General and Specific Comments:
As previously stated, the manuscript is compelling. However, I have some suggestions for improvement:
The presentation of the cases is not entirely clear. I recommend that the authors categorize the patients by age. For instance:
Table 1: Patient Characteristics according to Age
Age Count Median SD Min-Max
<18 5 15 18 0-99
>18 5 Same as above.
Sex ratio (M:F)
Age Ratio
<18 1:1.2
>18 1:1.2
Odontogenic tumors: type
Age Type Percentage
<18 AM XX%
>18 COF XX%
(Include other variables in a single table.)
Regarding Table 3, it seems unnecessary if all patients were LASV positive. Instead, consider incorporating variables related to LASV.
Pseudocarcinomatous hyperplasia is not entirely an odontogenic tumor, and ameloblastoma is not strictly fibrous bone tumor tissue.
The discussion, while informative, needs clarification. Please articulate hypotheses about the relationship between LASV and odontogenic tumors. Address questions such as: Is LASV closely linked to odontogenic tumors? Is LASV a significant risk factor for these tumors?
Figure 1 is insightful and well-described. Could there be an association between odontogenic tumors and the LASV virus in terms of tumorigenesis? Consider incorporating this into Figure 1.
Lines 307–308 are unclear; please provide a more detailed explanation.
Redraft the discussion to better correlate the main variables (odontogenic tumors and LASV)
Author Response
Reviewer 4
The manuscript authored by De Feo M. et al. is well done.
Summary:
In their study, the authors elucidate the association between the Lassa virus and odontogenic tumors, primarily focusing on ossifying fibroma. They present findings from nine cases, all of which underwent molecular studies to detect the presence of the Lassa virus.
General and Specific Comments:
As previously stated, the manuscript is compelling. However, I have some suggestions for improvement:
The presentation of the cases is not entirely clear. I recommend that the authors categorize the patients by age. For instance:
- Table 1: Patient Characteristics according to Age
Age Count Median SD Min-Max
<18 5 15 18 0-99
>18 5 Same as above.
Sex ratio (M:F)
Age Ratio
<18 1:1.2
>18 1:1.2
Odontogenic tumors: type
Age Type Percentage
<18 AM XX%
>18 COF XX%
(Include other variables in a single table.)
Response: We thank the reviewer for the the careful revision of the manuscript. Accordingly , we replaced the previous tables 1 and 2 with the revised new Table 1 following the reviewer's suggestions.
- Regarding Table 3, it seems unnecessary if all patients were LASV positive. Instead, consider incorporating variables related to LASV.
Response: Accordingly, we have removed this table and corrected the number of the other tables.
- Pseudocarcinomatous hyperplasia is not entirely an odontogenic tumor, and ameloblastoma is not strictly fibrous bone tumor tissue.
Response:
As the reviewer rightly commented, pseudocarcinomatous hyperplasia is defined as a marked proliferation of benign/reactive squamous epithelium in response to inflammation, infection, irradiation, or underlying malignancy. Pseudocarcinomatous hyperplasia can also be induced by a pre-existing tumor. In particular, the tissue that had this diagnosis of pseudocarcinomatous hyperplasia derived from the surgery of a recurrence of a previously operated ossifying fibroma. However, the resected masses are always very large in size, and we do not exclude the possibility that there may be a part of the ossifying fibroma that has not been found.
The reviewer's observation is correct, many thanks. Odontogenic tumors encompass a broader range of lesions arising from tooth-forming tissues and therefore include ameloblastoma, odontoma, cementoblastoma, ossifying fibroma and cementum ossifying fibroma while odontogenic fibrous bone tumors are a subset characterized by the predominance of fibrous tissue and bone involvement. Ameloblastomas are odontogenic tumors with varied subtypes based on the differences in histological, molecular, and clinical characteristics. Solid/multicystic ameloblastoma, on the other hand, may contain fibrous connective tissue among the solid epithelial islands and cystic spaces. However, the presence of fibrous tissue varies depending on the specific histological features of the tumor.
In summary, while fibrous components may be present in both desmoplastic and solid/multicystic ameloblastomas, they have not been considered the defining characteristic of these subtypes and therefore not been categorized as Odontogenic fibrous bone tumors but rather Odontogenic tumors.
We revealed only a patient showing ameloblastoma.
We have better specified the difference in the text and we have revised the text with the correct nomenclature updated to the latest revision of World Health Organization Classification of Head and Neck Tumors (2022).
References
- Vered, M.; Wright, J.M. Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Odontogenic and Maxillofacial Bone Tumours. Head Neck Pathol 2022, 16, 63–75, doi:10.1007/s12105-021-01404-7
- Vered M, Muller S, Heikinheimo K. IARC WHO Classification of Tumours. 4th Edition, Volume 9. Vol. 215. Lyon, France: IARC Press; 2017. Ameloblastoma; p. 8
- Lines 307–308 are unclear; please provide a more detailed explanation.
Response: Although these tumors are classified as odontogenic, we have observed and operated on patients with tumors lacking teeth, particularly the frequent recurrences that originate in edentulous maxillary bones because they were already extracted in previous surgical interventions for the same tumor.
However, this was an observation by Dr. de Feo and Dr. Dilu Tamba at the time of surgical resection, we removed it from the text to satisfy another reviewer's request as it was an unpublished observation.
- Figure 1 is insightful and well-described. Could there be an association between odontogenic tumors and the LASV virus in terms of tumorigenesis? Consider incorporating this into Figure 1.
- Redraft the discussion to better correlate the main variables (odontogenic tumors and LASV).The discussion, while informative, needs clarification. Please articulate hypotheses about the relationship between LASV and odontogenic tumors. Address questions such as: Is LASV closely linked to odontogenic tumors? Is LASV a significant risk factor for these tumors?
Response: We have created the new figure 6 whose description is included in the discussion, where we have schematized our hypothesis of LASV as a risk factor for the onset of OTs. We hope that it can be acceptable in the revised version of the manuscript.
In the discussion, we looked for correlations between LASV infection and pathologies documented in other tissues, trying to discuss possible parallels in OT thinking to the hypothetical mechanism that clearly should be investigated through in vitro experiments and in vivo models, which is also discussed.
Round 2
Reviewer 4 Report
Comments and Suggestions for Authors
Thank you for addressing all of my suggestions. This new revision has significantly improved the manuscript, rendering it more understandable and better constructed. However, in the PDF that I reviewed, Table 1 is overlapping and thus impossible to evaluate, as is Figure 1. Furthermore, two other figures, Figure 2 and Figure 3, are also overlapping. Additionally, Figure 4 lacks a description in the caption. I recommend reviewing these errors in your document.
Author Response
Dear Reviewer,
We would like to thank you again for the overall comments you provided in revising the manuscript, we are very happy with the final version.
We are truly sorry that you were not able to fully appreciate our corrections. We think there was a problem in the creation of the PDF, even though we saw it correctly.
However, we have double-checked everything and for your convenience we are attaching the pdf file without the corrections to make sure you can see it clearly.
We hope it is satisfactory.
Author Response File: 
Author Response.pdf
