Optimizing Outcomes in Total Femur Replacement: Complications, Management Strategies, and Lessons Learned

1. Summary

Thank you very much for taking the time to review this manuscript. Please find the detailed responses to your specific comments below and the corresponding corrections highlighted in the re-submitted files.

2. Point-by-point response to Comments and Suggestions for Authors

Comments 1: Abstract

1.      Clearly specify that this is a retrospective, single-center study.

2.      If applicable, indicate the study period and sample size explicitly.

3.      Temper causal or prescriptive language, emphasizing that findings are descriptive and associative.

Response 1: We specified that our study is retrospective and has been carried out in two independent centers. The sample size has been described in the Results section of the abstract: “ Results: Nineteen patients were included: 8 underwent TFR for oncological indications, while 11 had the procedure as a revision following failed endoprosthetic arthroplasty or trauma.” To emphasize that our findings are descriptive we added “In our experience effective complication management strategies should include;” at the begging of the conclusions section of the abstract. As well as a sentence “Implementing these strategies may improve patient outcomes and reduce the burden of complications associated with TFR.” at the end of that section to temper the prescriptive character of our conclusions. The study period is described later in the Result section : “A total of 19 patients who met the inclusion criteria were treated with a TFR between 2011 and 2023.”

Comments 2 :Introduction

The introduction is well framed and highlights the clinical complexity of TFR.

Consider briefly incorporating:

Comparative data from megaprosthesis or limb salvage literature, and

The known high complication burden associated with TFR.

Ensure that the study objective remains clearly defined as descriptive/analytical, rather than prescriptive.

Response 2: Thank you for pointing this out. Our Introduction highlights the high complication burden of TFR by saying: “In addition, TFR is often performed as a revision arthroplasty in patients who have already undergone multiple operations in the area. Those patients often have massive bone loss, poor bone quality and less compliant soft tissues [4]. These patient factors and the surgical technique are why TFR is associated with high complication rates [5]. The literature describes various complications including periprosthetic infection, mechanical failure, dislocations and others, often leading to revision surgeries or even amputation [4]. “ We focused on the comparative data in the Discussion of our manuscript. Example in the highlighted sections: “The most frequent complication of TFR described in the literature is the periprosthetic infection [8]. The incidence of this complication varies from 10 to 50% depending on the author [5,9]. In our study 21% of the patients suffered periprosthetic infection which seems to concur with the results previously described in the literature [10, 11].”

As for the last point we changed the language in the last paragraph of Introduction to clearly define that our study has a descriptive character per your suggestion. “For these reasons, we decided to write this article to present options for management of complications after the TFR procedure. We aimed to answer the following questions: 1.What were the most common complications in our experience? 2. How to can they be handled ? 3. What could be done to minimize the risk of complications?”

Comment 3: Study Design

Explicitly state whether patients were included consecutively.

Clarify whether the center represents a tertiary referral center, which may influence case complexity.

Response 3: We agree with this point, therefore we added to the manuscript that both hospitals are a tertiary referral centers, in the first paragraph of Methods section. We also describe that patients who met the inclusion criteria for our study were retrospectively identified from the hospital database. Both the inclusion and exclusion criteria are stated in the first paragraph of Methods in the manuscript.

Comment 4: Participant Characteristics

Provide more detail on:

Indications for TFR (oncologic vs. revision vs. trauma).

Baseline functional status.

Comorbidity burden (e.g., ASA, Charlson index if available).

Response 4: Participant characteristics are described in detail in the Result section of the manuscript. “Indications for the THR were metastatic tumors, local progression of metastasis with loosening of PFR, loosening of THR or TKR, periprosthetic fractures and inter-prosthetic fractures often accompanied by poor bone quality.” We also included a flow chart illustrating the reason for TFR and the number of patients for each of them- Figure 1 in the manuscript. When it comes to comorbidity burden and post-surgical functional status the information was not available for all the patients due to the retrospective nature of the manuscript , that is why we decided not to include it in the study. We added this point to the limitation section. We hope the explanations and the corrections we made will be found extensive enough.

Comment 5: Surgical and Perioperative Management

Clarify whether:

Surgical techniques were standardized or varied by surgeon.

Postoperative protocols (rehabilitation, infection prevention) were uniform

Response 5: In the first paragraph of Results we described that all oncologic cases were performed in one hospital by the same surgeon, and the same for the second hospital. Therefore the surgical techniques can be described as standardized. As for the post operative protocols the information was not available for all the patients, that is why we decided not to include it in the study. We added this point to the limitation section. We hope the explanations and the corrections we made will be found extensive enough.

Comment 6: Outcome Definitions

Clearly define:

Complication categories (e.g., infection, mechanical failure, dislocation).

Timeframe (early vs. late complications).

If functional outcomes are reported:

Specify the measurement tools used (e.g., MSTS, HHS).

Response 6: In Introduction we mentioned that “Some authors have used the Henderson classification to divide the complications into five categories [6].” However, as stated in the Methods due to the number of patients we limited the analysis to descriptive methods, rather than defining categories for the encountered complications we described each patients complications in the table. We feel that this presentation of complications gave a clearer view and explanation as to why certain management options were utilized in each case.

Comment 7: Statistical Analysis

The descriptive approach is appropriate; however, consider:

Reporting effect sizes where applicable.

Clarifying handling of missing data.

If subgroup analyses are presented:

Specify whether they were predefined or exploratory.

Response 7: We’re in agreement that the descriptive approach is appropriate for our manuscript. We chose this as a predefined strategy minding the small sample size of our group. We realize that with our number of patients reporting any effect sizes would not be statistically significant. Therefore we didn’t perform an analysis of subgroups and the conclusions were drawn in a descriptive manner based on our experience with different management strategies used during the study. As the number of data we were able to collect varied between patients we focused on the data which we were able to collect for all cases presented in the study. The issue of subgroups was later described in our discussion “In the systematic review of TFR, the authors present that oncologic patients have higher rates of soft tissue failures, aseptic loosening, and structural failures. On the other hand, the study shows that non-oncologic patients have a higher rate of prosthetic infections and worse functional outcomes [8]. In this study, both oncologic and non-oncologic patients were included. We observed fewer complications and fewer revisions after TFR in oncological patients. Our hypothesis is that this may be caused by a lower number of revisions prior to TFR in oncologic patients.”

Comment 8: Results

1.      Patient Heterogeneity

The cohort likely includes heterogeneous indications.

Consider stratifying results by:

Oncologic vs. non-oncologic cases

Primary vs. revision procedures

2.      Complications

The reporting of complications is clinically valuable.

Consider:

Presenting complication rates with confidence intervals.

Clarifying timing and severity of complications.

3.      Functional Outcomes (if applicable)

Ensure consistency between:

Reported improvements and

Statistical significance.

Avoid language suggesting improvement without statistical support.

Response 8: As we explained in the previous response (7), the cohort included patients with different indications and different number of revision procedures prior to the TFR implantation. The number, timing and severity of complication also varied between patients. All that was taken into account in deciding to utilize a descriptive method of our results. To ensure clarity and better understanding we added a table presenting each patients: initial reconstruction, number of revisions prior to TFR, indication for TFR, type of TFR implant, complications, management of complications and number of revision surgeries post TFR.
Thank you for taking notice of the aspect of consistency between the reported improvements and statistical significance. In our manuscript we do not use the terms “significant” or “statistically” to avoid confusing the potential reader. We hope that the clarification will be found appropriate.

Comment 9: Discussion

1.      Causality

Emphasize that findings are observational and descriptive, not causal.

2.      Confounding and Heterogeneity

Expand on:

Differences in indications and patient profiles

Impact of baseline function and comorbidities

3.      Comparison with Literature

Strengthen comparison with:

Existing studies on megaprostheses and limb salvage surgery

Known complication rates in TFR

4.      Clinical Implications

The practical recommendations are useful but should be:

Framed as experience-based insights, not definitive guidelines

Response 9: We thank the Reviewer for these valuable and detailed comments, which have significantly improved the clarity and scientific rigor of our Discussion.

1.Causality

We agree and have revised the manuscript to clearly emphasize that our findings are observational and descriptive in nature, and that no causal relationships can be inferred.

2.Confounding and Heterogeneity

We have expanded the Discussion to better acknowledge heterogeneity within our cohort. In particular, we now highlight differences in surgical indications and the potential impact of baseline functional status and comorbidities as important confounding factors influencing outcomes.

3.Comparison with Literature

We have strengthened the comparison with the existing literature on megaprostheses and limb salvage procedures, as well as contextualized our complication rates.

4.Clinical Implications

We have revised the clinical implications to ensure they are clearly framed as experience-based insights derived from our cohort, rather than as definitive or generalizable guidelines.

We believe these revisions improve the balance and interpretability of the Discussion.

Comment 10: Limitations

Strengthen by explicitly including:

Single-center design

Retrospective nature

Small sample size (if applicable)

Heterogeneity of indications

Lack of standardized outcome measures

Limited adjustment for confounders

Absence of long-term follow-up (if applicable)

Response 10: We agree with this comment, the sample size, retrospective nature and absence of long-term follow up was already discussed in Limitations. We also empathized that “the patient documentation was not always complete due to prolonged treatment in different clinics. That may have affected the amount of information collected about diagnosis, revisions, and other treatment prior to TFR”. We added “Finally, our study lacks of standardized outcome measures.” Due to the retrospective data collection we weren’t able to include functional measurement tools in our study.

Comment 11: Conclusions

The conclusions are appropriate but should be slightly moderated.

Suggested refinement:

Instead of strong prescriptive language, consider:

“These findings suggest that total femur replacement remains a high-risk but viable limb salvage option, with outcomes closely influenced by complication profiles and patient-specific factors. Careful patient selection and individualized management strategies appear essential to optimize outcomes.”

Response 11: We took into consideration the refinement and additionally modified the language used in the Conclusion section to make it less prescriptive.

Comment 12: Recommendation of Additional Literature

To strengthen the broader mechanistic and rehabilitation context, consider including:

Effects of Orthopedic Manual Therapy on Pain Sensitization in Patients with Chronic Musculoskeletal Pain: An Umbrella Review with Meta-Meta-Analysis

Correlation between the Altered Gut Microbiome and Lifestyle Interventions in Chronic Widespread Pain Patients: A Systematic Review

These may support discussion on individual variability and recovery processes.

Response 12: Thank you for this remark, we agree that elaborating literature broadens the perspective of the study. For this reason, we included some of the suggested literature in the article.

4. Response to Comments on the Quality of English Language

Point 1: The manuscript is written in clear academic English.

Minor editorial refinement may be beneficial during copyediting.

Tables and figures are generally clear and appropriate.

Response 1:   Thank you for this comment. We agree that an editorial refinement would be beneficial. During editing we focused on ensuring that the language, study objective and conclusions remains descriptive rather than prescriptive per your recommendation.

5. Additional clarifications

1. Summary

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding corrections highlighted in the re-submitted files.

2. Point-by-point response to Comments and Suggestions for Authors

Comments 1: TFR is not a rare procedure. It is a commonly undertaken orthopedic surgical procedure. Further, the complications observed following this surgery are also well known due to which how can the authors substantiate carrying out a study with a sample size of 19 patients.

Response 1: Thank you for this comment. Even though TFR is not a rarely undertaken procedure most of the existing original articles on TFR, many of them cited in our manuscript, describe groups of around 15 patients. Many studies published in the last 10 years included less than 20 patients (Sevelda F. et al. 11 cases, Toepfer A. et al. 18 cases, Adzhar AL et al. 10 cases), therefore we can describe our sample size as adequate for carrying out a study. We agree that the complications following TFR are well known, however our study shows how each patients complications, which often lead to revision surgeries, reasons for which are also described, were managed, rather than focusing on general ways to manage the complication. Additionally, we showcase a patient who suffered complications due to an allergy to metals and explore means to prevent and manage such situations, which isn’t an often described topic. We hope that this explanation addresses the Reviewer’s concerns.

Comments 2: In the introduction section, provide descriptions of the incidence of various complications following TFR with appropriate citations to the literature. Additionally, provide details on which of these complications is preventable and the precautions to be taken to reduce the risk. Back up these statements with appropriate references. Also, state the types of implants used for TFR and whether the complications rate differ between the implant types.

Response 2: We took your comment under consideration. Our introduction focuses on the TFR procedure and the evolving indications for it. We briefly mention the complications which as stated in the previous response are well known in the literature. As the last paragraph of introduction states “We aimed to answer the following questions: 1.What were the most common complications in our experience? 2. How to can they be handled ? 3. What could be done to minimize the risk of complications?”. Therefore we described the incidence of complication and compared it to existing literature in the discussion section of our manuscript.

The types of implants used are listed in the manuscript as well as in the Table. Due to the different number of each implant and the use of both standard and dual- mobility bearing we didn’t have reliable data to describe whether the complication rates differ between implant types.

Comment 3: In the methods section, "We obtained an IRB approval number AKBE/59/13" should be paraphrased. We obtained approval from IRB with the number...

Response 3: We agree and have accordingly modified the text to: “We obtained approval from IRB with the number AKBE/59/13”.

Comment 4: The study was carried out in 2 different hospitals. How may surgeons were involved in operating these patients? Their education, experiences and any differences in the learning curve should be explored.

Response 4: In the results section we mention that our study collected data from two independent hospitals, both being tertiary referral centers. All TFR surgeries were carried out by two surgeons, which we discuss at “ All non-oncologic patients were operated in one hospital by the same surgeon except for one case where intramedullary TFR was utilized - this patient was treated in the clinic where oncologic TFR were performed. There were 8 cases of metastatic tumors as primary diagnosis. All oncologic cases were performed in one hospital by the same surgeon.”

Comment 5: In the results section, the reasons for patients who underwent revisional surgery should be mentioned.

Response 5: Thank you for this important remark, we agree that identifying the indication for the surgery is crucial for fully understanding each individual case. That is why in the Table 1 we included the initial indication for the surgery. What is more, in the table we describe which complications required revision surgery. We hope that the information will allow the reader to fully comprehend the reasoning for the surgery (both initial and revision).  

Comment 6: Please expand SPACER and VAC when they appear for the first time

Response 6: Thank you for pointing this out. We adequately expanded SPACER to Antibiotic-Loaded Acrylic Cement Spacer and VAC to Vacuum-Assisted Closure therapy in the Results section of our manuscript.

Comment 7: With such a small number, statistically speaking, percentages (%) should not be calculated. Please remove stating the percentages.

Response 7: We thank the Reviewer for this thoughtful comment regarding the use of percentages with a small sample size. We agree that, in some contexts, percentages derived from limited observations may be misleading if presented without appropriate context.

However, in this case, we have chosen to retain the percentage values alongside the absolute numbers for the following reasons. First, reporting percentages facilitates comparison with previously published studies in this field, where proportions are commonly used even in small cohorts. Second, percentages in the manuscript are accompanied by the corresponding raw counts, ensuring full transparency of the underlying data. Third, the percentages are used descriptively rather than inferentially, and no statistical conclusions are drawn based on them.

In light of these considerations, we believe that retaining percentages together with absolute values provides a clearer and more informative presentation for readers.

We hope this clarification addresses the Reviewer’s concern.

Comment 8: In the methods section, provide details on the standard operating procedures that are being followed in each of the included hospitals when patients are being posted for TFR.

Response 8: Thank you for this comment. In the described cases the operating procedures had to be individualized due to their complexity and the fact that in 15 cases TFR was performed after an initial reconstruction ( THR, TKR, PFR). From those cases, 10 patients underwent previous to TFR revision surgeries which further complicated the approach and surgical difficulty of the TFR procedure.

Comment 9: In the discussion section, state the strengths of your study by mentioning the way your study differs from existing studies.

Response 9: Thank you for your advice. We introduced the suggested changes and summarized the strengths of the study. We hope the changes we made will be found extensive enough.

Comment 10: Please keep conclusion section concise without bullet points.

Response 10: Thank you for pointing this out! We made the conclusions more concise and deleted the bullet points.

4. Response to Comments on the Quality of English Language

Point 1: Quality of English Language

( ) The English could be improved to more clearly express the research.

(x) The English is fine and does not require any improvement.

Response 1:    We thank you for describing the language quality as not in need of improvements.

5. Additional clarifications

We hope that the changes we made, guided by your useful suggestions, will improve the

quality of our manuscript.

Kind regards,

Authors