Carnitine insufficiency is associated with fatigue during lenvatinib treatment in patients with hepatocellular carcinoma

Hironao Okubo; Hitoshi Ando; Kei Ishizuka; Ryuta Kitagawa; Shoki Okubo; Hiroaki Saito; Shigehiro Kokubu; Akihisa Miyazaki; Kenichi Ikejima; Shuichiro Shiina; Akihito Nagahara

doi:10.1371/journal.pone.0229772

Peer Review History

Original SubmissionNovember 21, 2019
10 Dec 2019 Decision Letter - Tatsuo Kanda, Editor PONE-D-19-32377 Carnitine insufficiency is associated with fatigue during lenvatinib treatment in patients with hepatocellular carcinoma PLOS ONE Dear Dr. Okubo, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. This manuscript seems to be important in this area. 1. Authors should describe the status of HBsAg and anti-HCV in table 1, and discuss their influence. 2. Major problem is that the number of patients is too small, and authors should increase the number of patients to at least 20. We would appreciate receiving your revised manuscript by Jan 24 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Tatsuo Kanda, M.D., Ph.D. Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements: Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Thank you for including your ethics statement in the manuscript Methods section: 'The study was approved by the ethics board of our university (Jundaiirin 2018193) and was performed in accordance with the 1964 Declaration of Helsinki and its later amendments.' a. Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study. b. Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”). For additional information about PLOS ONE ethical requirements for human subjects research, please refer to http://journals.plos.org/plosone/s/submission-guidelines#loc-human-subjects-research 3. We noticed you have some minor occurrence(s) of overlapping text with the following previous publication(s), which needs to be addressed: https://doi.org/10.1007/s00520-018-4521-6 https://doi.org/10.1371/journal.pone.0196747 https://doi.org/10.3109/00498254.2010.494201 In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the Methods section. Further consideration is dependent on these concerns being addressed. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors described about carnitine defficiency due to administration of lenvatinib, and efficatiy of levocarnitine supplementation in patients with hepatocellular carcinoma. Although a long treatment duration of lenvatinib is important for improvement of the patients prognosis, it is not easy to manage various adverse effects. This study showed one of the way of overcoming lenvatinib related fatigue. However some problems remain before publish in this manuscript. In Figure 4, the authors showed the correlation between BFI and AC/FC ratio in Day 14, and Day 28. Please add the figure of the correlation between BFI and AC/FC ratio at baseline. If correlation was not showed at baseline, please discuss the cause of this phenomenon. Please insert reference to discussion section, line 256. Reviewer #2: The authors tried to evaluate the relationship between carnitine levels and fatigue during lenvatinib treatment and found there were significant correlations between the plasma AC/FC ratio and the change in the BFI score at days 14 and 28. The paper is well written and organized, however, there are several concerns in the study. Major comments. As the authors mentioned in the limitations, the study cohort is too small. The reviewer would suggest that the authors evaluate ATP or energy charge level and/or OCTN functions of the patients. Detailed analysis using more parameters or translational experiments might add strength in the study regardless of the cohort size. The authors should provide information about treatment response and its relationship with the carnitine levels. The comparison of AC/FC levels between sorafenib and lenvatinib would be of interest. Although the BFI improved after the supplementation, AC/FC did not decrease. The authors conclude the well correlation between AC/FC and BFI during the treatment and they should discuss why this happened (why the AC/FC did not improve after the supplementation). ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0229772.r001
Revision 1
14 Jan 2020 Author Response Response to the Editor 11 January 2020 Dr. Tatsuo Kanda Academic Editor PLOS ONE Please find attached a copy of our revised manuscript entitled “Carnitine insufficiency is associated with fatigue during lenvatinib treatment in patients with hepatocellular carcinoma”, which we would like to resubmit for publication in PLOS ONE. We would like to thank the academic editor and the reviewers for their helpful comments. We have implemented the suggested changes and trust that our manuscript is now suitable for publication in your journal. Please find below a detailed description of the revisions made to the manuscript in our point-by-point responses to the comments from the reviewers. Yours sincerely, Hironao Okubo, MD, PhD Department of Gastroenterology Juntendo University Nerima Hospital Response to academic editor 1) Authors should describe the status of HBsAg and anti-HCV in table 1, and discuss their influence. Response: Thank you for your valuable comments. In accordance with the comment, we have added information about the etiology, which includes the presence or absence of HBs-Ag/HCV-Ab, in Table 1 and the Discussion section (lines 256–258 as follows: There was a strong correlation between BFI and AC/FC ratio at day 28 existed regardless of the presence or absence of viral hepatitis, whether it was a viral infection or other causes (r = 0.840 and r = 0.773, respectively). 2) Major problem is that the number of patients is too small, and authors should increase the number of patients to at least 20. Response: In accordance with the advice, we added the two most recent cases, and the data from 20 patients were reanalyzed. The revised results further support our conclusion. #Response to reviewer 1 1) In Figure 4, the authors showed the correlation between BFI and AC/FC ratio in Day 14, and Day 28. Please add the figure of the correlation between BFI and AC/FC ratio at baseline. If correlation was not showed at baseline, please discuss the cause of this phenomenon. Response: In accordance with the comment, we added the data for the correlation between BFI and the AC/FC ratio at baseline to Figure 4 of the revised manuscript. We found that there was a nearly significant positive correlation between the two variables (Fig 4A; r = 0.410, p = 0.073). This description was added to the revised manuscript (lines 200-202). 2) Please insert reference to discussion section, line 256. Response: In accordance with the reviewer’s advice, we have added the following reference to the Discussion (line 281 in the revised manuscript): Takahashi A, Moriguchi M, Seko Y, Ishikawa H, Yo T, Kimura H, et al. Impact of relative dose intensity of early-phase lenvatinib treatment on therapeutic response in hepatocellular carcinoma. Anticancer Res. 2019;39:5149-56. #Response to reviewer 2 1. As the authors mentioned in the limitations, the study cohort is too small. The reviewer would suggest that the authors evaluate ATP or energy charge level and/or OCTN functions of the patients. Detailed analysis using more parameters or translational experiments might add strength in the study regardless of the cohort size. Response: Thank you for the insightful and constructive comment. We agree with the comment, but evaluation of ATP/energy charge level or OCTN functions is extremely difficult in patients with cancer in clinical practice. Therefore, in accordance　with the academic editor’s advice, we added the additional two cases and re-analyzed the data for all 20 patients. We believe that our present clinical data are valuable and worth publishing in PLOS ONE. 2. The authors should provide information about treatment response and its relationship with the carnitine levels. Response: In accordance with the comment, we have conducted an additional analysis about the relationship between the treatment response and carnitine levels. The treatment responses were added to Table 1, and we discussed the relationship in the revised manuscript (lines 305–310) as follows: In addition, it is important to consider the type of patients who are recommended to receive carnitine supplementation. Because the baseline plasma AC/FC ratio in non-responders (SD and PD) tended to be higher compared with that of responders (CR and PR) (p = 0.057), it might be better to consider levocarnitine supplementation in patients with a high AC/FC ratio to retain the relative lenvatinib dose intensity. 3. The comparison of AC/FC levels between sorafenib and lenvatinib would be of interest. Response: We thank the Reviewer for this insightful comment. In accordance with this comment, we added the presumptive difference in the inhibitory effect on OCTN2 between lenvatinib and sorafenib, which would affect the AC/FC level, into the Discussion section of the revised manuscript (lines 275–278) as follows: However, because more fatigue was reported during lenvatinib therapy compared with sorafenib [3], it is possible that lenvatinib’s inhibitory effect on OCTN2 is stronger compared with that of sorafenib. 4. Although the BFI improved after the supplementation, AC/FC did not decrease. The authors conclude the well correlation between AC/FC and BFI during the treatment and they should discuss why this happened (why the AC/FC did not improve after the supplementation). Response: We would like to express our strong appreciation to reviewer 2 for this comment. As the reviewer pointed out, the AC/FC ratio did not necessarily improve after the levocarnitine supplementation. We think that the placebo effect, including the recognition of dose reduction, might influence the BFI score especially in some patients with dose reduction. We provided this interpretation on lines 296–298 of the revised manuscript. Moreover, for reader’s convenience, we have changed Figure 5, which separately shows patients with and without dose reduction. #Response to Journal Requirement 1. We have checked that our manuscript meets STROBE statement. 2. a) As pointed out, the notation has been changed as follows: This study was approved by the Ethics Review Board of Juntendo University Faculty of Medicine (Jundai-Irin No-2016135) and was performed in accordance with the 1964 Declaration of Helsinki and its later amendments. b) In accordance with the comment, we have inserted the same text to the “Ethics Statement”. 3. Thank you for pointing some minor occurrences of overlapping text. The notation has been changed as follows. Lines 68–69: Patients with cancer occasionally experience fatigue and general malaise before and after treatment, which is described as cancer-related fatigue. Line 98–99: This study was approved by the Ethics Review Board of Juntendo University Faculty of Medicine Line 185–189: The box spans data between two quartiles (IQR, interquartile range), and the bold line represents the median. The ends of the whiskers represent the largest and smallest values that are not outliers. Attachments Attachment Submitted filename: Response to Reviewers OKUBO.rtf https://doi.org/10.1371/journal.pone.0229772.r002
21 Jan 2020 Decision Letter - Tatsuo Kanda, Editor PONE-D-19-32377R1 Carnitine insufficiency is associated with fatigue during lenvatinib treatment in patients with hepatocellular carcinoma PLOS ONE Dear Prof. Okubo, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. We would appreciate receiving your revised manuscript by Mar 06 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Tatsuo Kanda, M.D., Ph.D. Academic Editor PLOS ONE [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Thank you for revising the problem. The correlation coefficient between BFI and AC/FC ratio is increases from baseline to day 28 in Figure 4. I think it is consistent because fatigue is relatively weak at baseline. Revised manuscript satisfies my requirement. Thank you. Reviewer #2: The authors have fulfilled each of the major compulsory revisions and modified the manuscript as requested. I have the following further suggestions that in my opinion will improve the quality of the manuscript. In the study, authors measured urine/plasma AC/FC. The reviewer was wondering if they could describe which marker was the most useful in the real-world clinical setting: the reason, speculation, and how often it should be monitored. Please add this information in the discussion section. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0229772.r003
Revision 2
3 Feb 2020 Author Response #Response to reviewer 2 1. In the study, authors measured urine/plasma AC/FC. The reviewer was wondering if they could describe which marker was the most useful in the real-world clinical setting: the reason, speculation, and how often it should be monitored. Please add this information in the discussion section. Response: Thank you for the insightful comment. In accordance with the comment, we discussed the utility of the plasma AC/FC ratio in the real-world clinical setting in the revised manuscript (lines 311–316) as follows: Throughout the study period, only the plasma AC/FC ratio among all of the markers (plasma FC, plasma AC, urine FC, urine AC levels, and urine AC/FC ratio) was associated with BFI (data not shown). Therefore, only the plasma AC/FC ratio seems to be a useful marker during lenvatinib therapy. As mentioned above, the baseline plasma AC/FC ratio seems to be useful for predicting incomplete treatment with lenvatinib. Attachments Attachment Submitted filename: renamed_31884.rtf https://doi.org/10.1371/journal.pone.0229772.r004
5 Feb 2020 Decision Letter - Tatsuo Kanda, Editor PONE-D-19-32377R2 Carnitine insufficiency is associated with fatigue during lenvatinib treatment in patients with hepatocellular carcinoma PLOS ONE Dear Prof. Okubo, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== Authors should make a list of each patients'characteristics and data by an excel file and submit the excel file as a supplementary file with manuscript again. ============================== We would appreciate receiving your revised manuscript by Mar 21 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Tatsuo Kanda, M.D., Ph.D. Academic Editor PLOS ONE [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0229772.r005
Revision 3
12 Feb 2020 Author Response Response to the Editor 12 February 2020 Dr. Tatsuo Kanda, Academic Editor PLOS ONE Dear Dr. Kanda, Please find attached a copy of our revised manuscript titled “Carnitine insufficiency is associated with fatigue during lenvatinib treatment in patients with hepatocellular carcinoma”, which we would like to resubmit for publication in PLOS ONE. We would like to thank for the helpful comment. We have added a supplementary file including the patient characteristics and data, and we trust that our manuscript is now suitable for publication in your journal. Yours sincerely, Hironao Okubo, MD, PhD Department of Gastroenterology Juntendo University Nerima Hospital #Response to the academic editor 1. Authors should make a list of each patients' characteristics and data by an excel file and submit the excel file as a supplementary file with manuscript again. Response: Thank you for the helpful comment. In accordance with the comment, we have added a supplementary file including the patient characteristics and data, and we trust that our manuscript is now suitable for publication in your journal. In addition, we have added the supporting information into the revised manuscript (lines 330–331) as follows: Supporting information S1 Data. Patient characteristics and data. Attachments Attachment Submitted filename: R3 Response to the Editor.rtf https://doi.org/10.1371/journal.pone.0229772.r006
14 Feb 2020 Decision Letter - Tatsuo Kanda, Editor Carnitine insufficiency is associated with fatigue during lenvatinib treatment in patients with hepatocellular carcinoma PONE-D-19-32377R3 Dear Dr. Okubo, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. With kind regards, Tatsuo Kanda, M.D., Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0229772.r007
Formally Accepted
19 Feb 2020 Acceptance Letter - Tatsuo Kanda, Editor PONE-D-19-32377R3 Carnitine insufficiency is associated with fatigue during lenvatinib treatment in patients with hepatocellular carcinoma Dear Dr. Okubo: I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Tatsuo Kanda Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0229772.r008

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