A Locally Advanced NSCLC Patient Harboring a Rare KIF13A-RET Fusion Benefited from Pralsetinib: A Case Report
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis manuscript presents an intriguing case study of a 58-year-old patient with stage IIIA non-small cell lung cancer (NSCLC) harboring a rare KIF13A-RET fusion, who received adjuvant treatment with pralsetinib monotherapy. The case is notable for several reasons and offers valuable insights into the potential efficacy of targeted therapies for rare gene mutations in NSCLC, as well as the utility of circulating tumor DNA (ctDNA) monitoring in detecting recurrence.
In conclusion, this case study provides valuable preliminary evidence supporting the use of pralsetinib and ctDNA monitoring in NSCLC patients with rare gene mutations. While the findings are promising, further research is essential to confirm these results and establish standardized treatment protocols.
Author Response
Thank you for your thoughtful and positive feedback on our manuscript. We appreciate your recognition of the significance of this case study involving a 58-year-old patient with stage IIIA non-small cell lung cancer (NSCLC) harboring a rare KIF13A-RET fusion, who received adjuvant treatment with pralsetinib monotherapy.
We are pleased that you found the case notable and valuable in providing insights into the potential efficacy of targeted therapies for rare gene mutations in NSCLC, as well as the utility of circulating tumor DNA (ctDNA) monitoring in detecting recurrence.
As you correctly highlighted, while the findings are promising, further research is indeed essential to confirm these results and establish standardized treatment protocols. We have emphasized the need for prospective studies in our discussion section to validate our observations and to further investigate the potential of pralsetinib and ctDNA monitoring in this patient population.
Thank you once again for your encouraging comments and insightful suggestions. If you have any further feedback or recommendations, we would be happy to consider them.
Reviewer 2 Report
Comments and Suggestions for AuthorsThis is a case report in a single level N2 stage IIIA patient with adenocarcinoma that was primarily operated. Preoperative staging is not described, it is unclear, whether PET_CT and MRI of the brain were done to rule out distant metastases. Pathologic stage at surgery was N2 single level. The patient was started on Pralsetinib 400 mg and than dose reduced to selpercatinib 300 mg, please decide which medication the patient was been given. most likely pralsetinib is meant, as 300 mg is the first dose level when dose reduction has to take place.
The study by Li N et al. showed that only in 25% of patients in stages I to III that preoperatively ctDNA was measurable. Therefore, it should be stated in the discussion, that the sensitivity of assays urgently needs to be improved.
it should be also discussed, that the standard of care of patients with stage III after surgery should be chemotherapy and most likely not, even in cases with a high PD-L1 expression, adjuvant PD-1 or PD-L1 therapy. The data of the case with a median DFS are suggestive of a positive impact of adjuvant pralsetinib with a DFS of 27 months. If one compares for example with the ADAURA study, the PFS of the stage IIIA patients was much inferior in the control arm compared to the 27 months. HOwever, it should be stressed, that prospective studies like the ADAURA and ALINA studies are necessary to clarify this question.
Author Response
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1. Summary |
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Thank you for your thorough review of our manuscript and your valuable suggestions. Based on your guidance, we have made the following revisions and improvements. Please find the detailed responses below and the corresponding revisions in track changes in the re-submitted files. |
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2. Point-by-point response to Comments and Suggestions for Authors |
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Comments 1: Preoperative staging is not described, it is unclear, whether PET_CT and MRI of the brain were done to rule out distant metastases. |
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Response 1: Thank you for your detailed review of our manuscript and your valuable comments. Regarding the description of preoperative staging, we have revised the manuscript to include this information. Specifically, our patient underwent a brain MRI preoperatively to rule out brain metastases. This detail has been added to the revised manuscript and highlighted using track changes. We appreciate your feedback, which has helped improve the completeness and clarity of our manuscript. If you have any further suggestions or comments, please feel free to let us know. Please see revised manuscript tracked version line 56. |
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Comments 2: The patient was started on Pralsetinib 400 mg and than dose reduced to selpercatinib 300 mg, please decide which medication the patient was been given. most likely pralsetinib is meant, as 300 mg is the first dose level when dose reduction has to take place. |
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Response 2: Thank you for your observation. You are correct that the correct RET-TKI mentioned should be Pralsetinib, not Selpercatinib. We apologize for the oversight. The sentence in the manuscript will be revised to reflect this correction accurately. The correct information is that the dose adjustment was for Pralsetinib, changing from 400 mg/d to 300 mg/d. Please see revised manuscript tracked version line 84 and 94. Comments 3: The study by Li N et al. showed that only in 25% of patients in stages I to III that preoperatively ctDNA was measurable. Therefore, it should be stated in the discussion, that the sensitivity of assays urgently needs to be improved. Response 3: Thank you for your insightful comment regarding the sensitivity of ctDNA assays. We have addressed this issue by citing the study by Li N et al., which demonstrated that ctDNA was measurable preoperatively in only 24.8% of patients in stages I to III. This reference has been incorporated into the discussion to highlight the current limitations of ctDNA detection sensitivity and the urgent need for improvement in assay sensitivity. Please see revised manuscript tracked version line 193-202.
Comments 4: It should be also discussed, that the standard of care of patients with stage III after surgery should be chemotherapy and most likely not, even in cases with a high PD-L1 expression, adjuvant PD-1 or PD-L1 therapy. The data of the case with a median DFS are suggestive of a positive impact of adjuvant pralsetinib with a DFS of 27 months. If one compares for example with the ADAURA study, the PFS of the stage IIIA patients was much inferior in the control arm compared to the 27 months. HOwever, it should be stressed, that prospective studies like the ADAURA and ALINA studies are necessary to clarify this question. Response 4: Thank you for your valuable comments and suggestions regarding the standard of care for stage III patients after surgery. We have revised the discussion to address the point that adjuvant standard treatment regimen for early and locally advanced RET-positive NSCLC was still platinum-based doublet chemotherapy. We have also included a discussion on the data from our case, which suggests a positive impact of adjuvant pralsetinib with a DFS of 27 months. When compared to the ADAURA study, where the DFS for stage IIIA patients in the control arm was much inferior, our findings are noteworthy. Additionally, we have emphasized the necessity of prospective studies, such as ADAURA, to clarify this question and validate our observations. Please see revised manuscript tracked version line 147-166.
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Reviewer 3 Report
Comments and Suggestions for AuthorsThe Authors present a case of an operated stage IIIA RET-rearranged lung adenocarcinoma displaying a remarkable response to adjuvant treatment with the RET-TKI Pralsetinib. The case is interesting, as real-world data on treatment of NSCLC driven by rare genomic alterations, such as RET-fusions are limited. This is particularly true for adjuvant treatment of operable RET-rearranged NSCLC, for which no guidelines are currently existing. Furthermore, the presented NSCLC harbored the rare type of RET fusion, KIF13A-RET, for which not much is known in terms of clinical responsiveness to targeted treatment, as opposed to the more common KIF5B-RET and CCDC6-RET fusions. Yet, the manuscript requires some revision before being acceptable for publication. Especially the case description needs attention, as several sentences are confusing for the readers.
SPECIFIC POINTS
Case presentation
Line 50, “Chest computed tomography (CT) revealed solid mass”: It should be “Chest computed tomography (CT) revealed a solid mass”.
Line 52-54, “There is a small amount of pleural effusion in the right chest cavity (Figs 1A, 1B and 1C). The pathology report from the CT-guided lung 53 mass biopsy indicates NSCLC”. Since the rest of the case description is (rightfully) in past tense, these two sentences should also be in past tense.
Line 57, “the patient underwent curative surgery for right lower lung cancer”: Please indicate what kind of surgical operation was performed (lobectomy? Segmental surgery? Other type of pulmonary resection?).
Line 62-63, “the disease is diagnosed as stage IIIA adenocarcinoma of the lung (pT2bN2M0).”: On line 52 it is stated that radiographically the tumor was staged as cT2aN2M0. Thus, it should be specified why it became pT2b after pathological examination of the resected tumor and not pT2a as preoperatively evaluated. Was the tumor > 40 mm at gross pathology examination?
Line 64-66, “Mutation profiling of peripheral blood using ctDNA and unstained FFPE tumor tissue targeted next-generation sequencing (NGS) for 139 cancer-related genes was performed at GENSEEQ (Nanjing, China)”: several issues need clarification in this sentence and the rest of the paragraph describing the methods used for NGS analyses of tumor tissue and ctDNA:
- Phrased like this, it sounds like the Authors have profiled the blood and not the ctDNA … I assume the ctDNA examined by NGS was obtained from plasma, not the entire blood, to avoid contamination by DNA from intact blood cells that are separated in the buffy coat. Thus, if that’s the case, the sentence could be more correctly formulated as: “Mutation profiling of ctDNA from plasma and of DNA obtained from formalin-fixed paraffin-embedded (FFPE) tumor tissue sections were obtained by next-generation sequencing (NGS) of 139 cancer-related genes performed at GENSEEQ (Nanjing, China)”.
- It remains unclear though, how the RET-fusion was identified. The NGS panel and platform used at GENSEEQ on the tissue specimen and on ctDNA should be described more in detail. Was the same NGS method used for both tissue and ctDNA?
- On line 75, the Authors mention LungTrak ctDNA for the longitudinal testing of ctDNA. Was this also used for testing ctDNA the first time?
- Was the RET fusion detected using a DNA-and RNA-NGS panel that identifies fusions transcripts or was it detected by an entirely DNA-based NGS method that reveals fusions by more laborious DNA sequencing?
- Finally, what was the sequencing platform used for the study: Illumina, IonTorrent ThermoFisher, other?
Line 68-69, “CtDNA was not identified in the peripheral blood”: to avoid misunderstandings with the longitudinal testing of ctDNA described further down, please specify when this blood sample was taken. Before operation, right after operation or later?
Line 72, “… the patient was started on oral pralsetinib at a dose of 400 mg/d on postoperative day 84”: The treatment with Pralsetinib began almost 3 months after operation, Was a ctDNA tested at baseline (i.e., day 84 after operation?) as initial time points for the longitudinal monitoring of ctDNA?
Line 74, “prompting a dose adjustment of selpercatinib to 300 mg/d”: this RET-TKI has not been mentioned before in the case presentation, presumably the Authors mean dose adjustment of Pralsetinib from 400 to 300 mg/d.
Line 74-76, “Upon the 74 patient’s request, ctDNA was monitored at periodic intervals using LungTrak ctDNA testing”: As mentioned above, the description of mutational testing is unclear throughout the text. Being ctDNA-based, can the LungTrak ctDNA testing monitor gene fusions in such as low amount of ctDNA as the one circulating in plasma? Or does the method use RNA fusions transcripts to detect gene fusions? In that case, it seems strange to call it ctDNA. Or were the TP53, APC and MYC mutations also used as ctDNA? The issue of which genomic alterations were used as ctDNA and how they were detected should be explained.
Line 77, “both 0.0% MAF”: the abbreviation MAF should be spelled out the first time before being utilized.
Line 83, “After 1 month of regular selpercatinib intake”: The Authors insist on Selpercatinib. Is this another mix-up (i.e., it should have been Prasletinib) or did they switch to Selpercatinib? Please clarify.
Line 89-90, “In November 2023, two months after treatment with bevacizumab in conjunction with the original regimen”: Again, to avoid misunderstandings in light of the above-mentioned issues, does this mean Pralsetinib or Selpercatinib?
Figure 4, representing the “longitudinal ctDNA levels monitoring”: The MS would greatly benefit in clarity by adding to the dynamic ctDNA monitoring in the figure (for ex. above the ctDNA line) the clinical time course including operation time point, baseline for Pralsetinib, treatment responses and progressions as well as initiation and response related to supplementing Bevacizumab to the patient.
Discussion
Line 118, “achieving a disease-free survival (DFS) of 27 months”: it would be more appropriate to call it here and in other parts of the MS (including the Abstract) “progression-free survival (PFS)”, as the radiologically assessed response is not complete, i.e., the disease is still there despite the PR or SD status observed at different time points.
Line 120-121, “first case documenting the utilization of RET inhibitor for adjuvant therapy following surgical intervention”: … utilization of a RET inhibitor ….
Line 128-129, “Additionally, RET fusion-positive patients typically have lower PD-L1 expression”: The statement should be supported by some reference(s).
Line 171-173: Among the limitations of ctDNA analysis the Authors should also mention the fact that not all genomic alterations are shedded into the blood and that liquid biopsies cannot detect phenotypic transformation of tumor tumor tissue as mechanism of treatment resistance and tumor progression.
Reference 7, Drilon et al. 2018: The text “Author 1, A.B. Title of Thesis. Level of Thesis, Degree-Granting University, Location of University, Date of Completion” does not seem to belong to the reference.
Comments on the Quality of English LanguageThe grammar requires attention. Moderate editing is required throughout the MS. Some adjustments are suggested in the Comments for Authors.
Author Response
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Response to Reviewer 3 Comments
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1. Summary |
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Thank you for your thorough review of our manuscript and your valuable suggestions. Based on your guidance, we have made the following revisions and improvements. Please find the detailed responses below and the corresponding revisions in track changes in the re-submitted files. |
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2. Point-by-point response to Comments and Suggestions for Authors |
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Comments 1: Line 50, “Chest computed tomography (CT) revealed solid mass”: It should be “Chest computed tomography (CT) revealed a solid mass”. |
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Response 1: Thank you for pointing this out. We agree with this comment. Therefore, we have made the suggested correction. The revised sentence now reads: " Chest computed tomography (CT) revealed a solid mass measuring 40mm × 30mm in the lower lobe of the right lung." Please see revised manuscript tracked version line 50. |
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Comments 2: Line 52-54, “There is a small amount of pleural effusion in the right chest cavity (Figs 1A, 1B and 1C). The pathology report from the CT-guided lung 53 mass biopsy indicates NSCLC”. Since the rest of the case description is (rightfully) in past tense, these two sentences should also be in past tense. |
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Response 2: Thank you for pointing this out. We agree with this comment. Therefore, we have made the suggested correction. The revised sentence now reads: " There was a small amount of pleural effusion in the right chest cavity (Figs 1A, 1B and 1C). The pathology report from the CT-guided lung mass biopsy indicated NSCLC. " Please see revised manuscript tracked version line 52-54. Comments 3: “the patient underwent curative surgery for right lower lung cancer”: Please indicate what kind of surgical operation was performed (lobectomy? Segmental surgery? Other type of pulmonary resection?). Response 3: Thank you for pointing out the need for clarification regarding the surgical procedure. We have revised the description to specify the type of surgery performed. The sentence now reads: " Following completion of relevant preoperative evaluations, the patient underwent curative right lower lobectomy and mediastinal lymph node dissection on March 9th 2021. " Please see revised manuscript tracked version line 57-59. Comments 4: “the disease is diagnosed as stage IIIA adenocarcinoma of the lung (pT2bN2M0).”: On line 52 it is stated that radiographically the tumor was staged as cT2aN2M0. Thus, it should be specified why it became pT2b after pathological examination of the resected tumor and not pT2a as preoperatively evaluated. Was the tumor > 40 mm at gross pathology examination? Response 4: Thank you for your insightful comments. We have revised the manuscript to address your concern regarding the discrepancy between the preoperative radiographic staging (cT2aN2M0) and the postoperative pathological staging (pT2bN2M0). The change in staging is due to the gross pathology examination, which revealed that the tumor size was 45 mm × 38 mm × 35 mm, exceeding the 40 mm threshold that differentiates T2a from T2b. This information has been included in the revised manuscript to clarify the reason for the staging upgrade. Please see revised manuscript tracked version line 63-64. Comments 5: The NGS panel and platform used at GENSEEQ on the tissue specimen and on ctDNA should be described more in detail. Was the same NGS method used for both tissue and ctDNA? the Authors mention LungTrak ctDNA for the longitudinal testing of ctDNA. Was this also used for testing ctDNA the first time? Was the RET fusion detected using a DNA-and RNA-NGS panel that identifies fusions transcripts or was it detected by an entirely DNA-based NGS method that reveals fusions by more laborious DNA sequencing? Finally, what was the sequencing platform used for the study: Illumina, IonTorrent ThermoFisher, other? Response 5: Thank you for your thorough and insightful comments. We have made several revisions to the manuscript to address the issues you raised regarding the NGS analyses of tumor tissue and ctDNA. Here are our responses to each point: Clarification of Sample Source: The original phrasing was indeed misleading. We have revised the sentence to more accurately reflect that ctDNA was obtained from plasma, not from whole blood, to avoid contamination by DNA from intact blood cells. The revised sentence now reads: “Mutation profiling of ctDNA from peripheral plasma collected one week after surgery and of DNA obtained from formalin-fixed paraffin-embedded (FFPE) tumor tissue sections was performed using next-generation sequencing (NGS).” RET-Fusion Identification: The identification of the RET-fusion was performed using the same DNA-based NGS panel for both tissue and ctDNA to ensure consistency. We have now included a detailed description of the NGS methods, including the panel used, in the case presentation the manuscript. LungTrak ctDNA Testing: For longitudinal testing, we used the LungTrak ctDNA assay, which was also employed for the initial ct DNA test. This has been clarified in the manuscript. Sequencing Platform: The sequencing platform used for this study was the Illumina platform. This information has been incorporated into the manuscript for clarity. Please see revised manuscript tracked version line 67-78. We appreciate your valuable feedback and hope the revised manuscript meets your expectations. Comments 6: “… the patient was started on oral pralsetinib at a dose of 400 mg/d on postoperative day 84”: The treatment with Pralsetinib began almost 3 months after operation, was a ctDNA tested at baseline (i.e., day 84 after operation?) as initial time points for the longitudinal monitoring of ctDNA? Response 6: Thank you for your insightful question regarding the baseline ctDNA testing. To clarify, the patient underwent the first ctDNA testing on postoperative day 7, which showed a negative result. However, due to the unavailability of the drug at that time, Pralsetinib treatment commenced only on postoperative day 84. During the period between the initial ctDNA test and the start of treatment, no additional baseline ctDNA tests were conducted. The result from the test performed on postoperative day 7 served as the initial reference point for the longitudinal monitoring of ctDNA.We have revised the manuscript to clearly specify these details and ensure that the timing of the baseline ctDNA test is accurately communicated. Please see revised manuscript tracked version line 77-78. Comments 7: “… the patient was started on oral pralsetinib at a dose of 400 mg/d on postoperative day 84”: The treatment with Pralsetinib began almost 3 months after operation, Was a ctDNA tested at baseline (i.e., day 84 after operation?) as initial time points for the longitudinal monitoring of ctDNA? Response 7: Thank you for your observation. You are correct that the correct RET-TKI mentioned should be Pralsetinib, not Selpercatinib. We apologize for the oversight. The sentence in the manuscript will be revised to reflect this correction accurately. The correct information is that the dose adjustment was for Pralsetinib, changing from 400 mg/d to 300 mg/d. Please see revised manuscript tracked version line 84 and 94. Comments 8: Representing the “longitudinal ctDNA levels monitoring”: The MS would greatly benefit in clarity by adding to the dynamic ctDNA monitoring in the figure (for ex. above the ctDNA line) the clinical time course including operation time point, baseline for Pralsetinib, treatment responses and progressions as well as initiation and response related to supplementing Bevacizumab to the patient. Response 8: Thank you for your insightful suggestion. We agree that including the clinical time course in the figure representing the dynamic ctDNA monitoring would significantly enhance the clarity of our manuscript. We will revise the figure to include the operation time point, baseline for Pralsetinib, progressions, as well as the initiation related to supplementing Bevacizumab. This will provide a comprehensive view of the patient's treatment timeline in relation to the ctDNA levels. Please see the revised Figure 4. Comments 9: Line 118, “achieving a disease-free survival (DFS) of 27 months”: it would be more appropriate to call it here and in other parts of the MS (including the Abstract) “progression-free survival (PFS)”, as the radiologically assessed response is not complete, i.e., the disease is still there despite the PR or SD status observed at different time points. Response 9: Thank you for your attention to our study and for your valuable suggestion. We understand your point regarding the suggestion to use progression-free survival (PFS) instead of disease-free survival (DFS) in our manuscript, including at line 118. Our study indeed demonstrates that patients achieved 27 months of disease-free survival after radical surgery, followed by recurrence and subsequent second-line treatment with bevacizumab.In our manuscript, we have opted to use the term DFS to reflect the period during which patients did not experience clinically evident disease recurrence post-surgery. Despite radiologically assessed partial response (PR) or stable disease (SD), our primary focus remains on the pathological status post-surgery and treatment response. Comments 10: “first case documenting the utilization of RET inhibitor for adjuvant therapy following surgical intervention”: … utilization of a RET inhibitor … Response 10: Thank you for your feedback and thorough review of our manuscript. We have noted your observation regarding the grammatical error in the phrase "first case documenting the utilization of a RET inhibitor for adjuvant therapy following surgical intervention." We have made the necessary corrections to ensure clarity and accuracy throughout the manuscript, including this specific section. Please see revised manuscript tracked version line 133. Comments 11: “Additionally, RET fusion-positive patients typically have lower PD-L1 expression”: The statement should be supported by some reference(s). Response 11: Thank you for your suggestion and careful review of our manuscript. We have incorporated an additional reference to support the statement. Please see revised manuscript tracked version line 140-143. Comments 12: Among the limitations of ctDNA analysis the Authors should also mention the fact that not all genomic alterations are shedded into the blood and that liquid biopsies cannot detect phenotypic transformation of tumor tumor tissue as mechanism of treatment resistance and tumor progression. Response 12: Thank you for your insightful feedback and careful review of our manuscript. We have revised the manuscript to include the limitation that "not all genomic alterations are shed into the blood, and liquid biopsies may not detect phenotypic transformations in tumor tissue as mechanisms of treatment resistance and tumor progression." Additionally, we have referenced relevant literature to support this statement.These updates address the important consideration you raised regarding the limitations of ctDNA analysis in our study. Please see revised manuscript tracked version line 193-202. Comments 13: Drilon et al. 2018: The text “Author 1, A.B. Title of Thesis. Level of Thesis, Degree-Granting University, Location of University, Date of Completion” does not seem to belong to the reference. Response 13: Thank you for bringing this to our attention and for your careful review of our manuscript. We apologize for the oversight regarding the reference "Drilon et al. 2018." The text "Author 1, A.B. Title of Thesis. Level of Thesis, Degree-Granting University, Location of University, Date of Completion" does not belong to the reference and has been removed from our manuscript. Please see revised manuscript tracked version line 244-245.
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3. Response to Comments on the Quality of English Language |
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Response: Thank you for your comments regarding the quality of the English language in our manuscript. We have carefully reviewed and revised the text to improve clarity, grammar, and overall readability. We believe these changes have significantly enhanced the quality of the manuscript.Please find the detailed revisions highlighted in track changes in the re-submitted files. We appreciate your feedback and the opportunity to improve our work. If you have any further suggestions, please feel free to let us know.
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Round 2
Reviewer 3 Report
Comments and Suggestions for AuthorsThe Authors have satisfactorily addressed all the initial comments from the first review of their MS. The latter deserves publication. The only two minor adjustments, I would like to suggest are:
- Remove the redundant numbers 0.10% and 0.21% from figure 4;
- In the Discussion, the Authors state that “the significant DFS and overall survival (OS) benefits of osimertinib in adjuvant treatment for EGFR-positive patients demonstrated in the ADAURA trial” has motivated their attempt with adjuvant Pralsetinib treatment in their patient. They correctly cite reference 11 (Herbst RS et al JCO 2023), which is mainly focused on the effect on DFS provided by Osimertinib. In terms of OS provided by adjuvant Osimerinib, the Authors should more correctly cite also Tsuboi M et al. NEJM 2023 (doi: 10.1056/NEJMoa2304594).
The Authors can easily make both suggested adjustments in the MS, when they receive the galley proof, without the need for another round of revision, as far as I am concerned.
Thank you for the opportunity to read this interesting case report.
Author Response
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1. Summary |
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Thank you again for your thorough review and valuable comments on our manuscript. We have carefully considered your suggestions and made the necessary revisions accordingly. The specific adjustments are as follows: |
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2. Point-by-point response to Comments and Suggestions for Authors |
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Comments 1: Remove the redundant numbers 0.10% and 0.21% from figure 4; |
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Response 1: Thank you for pointing this out. We agree with this comment. We have removed the redundant numbers 0.10% and 0.21% from Figure 4. |
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Comments 2: In terms of OS provided by adjuvant Osimerinib, the Authors should more correctly cite also Tsuboi M et al. NEJM 2023 (doi: 10.1056/NEJMoa2304594). |
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Response 2: Thank you for your insightful suggestion regarding the citation in the Discussion section. We have now included the citation of Tsuboi M et al. (NEJM 2023, doi: 10.1056/NEJMoa2304594) to more accurately reflect the impact of adjuvant osimertinib on overall survival (OS). We appreciate your guidance in ensuring that our manuscript provides a comprehensive and accurate representation of the relevant literature. Please see revised manuscript tracked version line 157-160.
Thank you again for your recognition and support of our work. If you have any further suggestions or require additional revisions, please do not hesitate to let us know.
