6/15/15. Dear Editorial Board,

Transcription

1 6/15/15 Dear Editorial Board, Thank you to the editor and reviewers for their thoughtful comments. We have revised the previously submitted manuscript by addressing all of the comments provided by the reviewers. Please see below for a response, noted in italic font, to each comment or critique provided. Please feel free to contact me with any further questions. Sincerely, Alvaro Martinez-Camacho, MD Division of Digestive and Liver Health Denver Health and Hospital Authority 660 Bannock St, MC 4000 Denver, CO Alvaro.martinez-camacho@dhha.org

2 Reviewer 1: The title is grand, but there is little description of the technical aspect. The authors say they use US most, but have not described the US technique used in difficult cases in more details. Thank you for pointing out the lack of extensive technical discussion in the manuscript. Our intent was not to provide a technical manual for RFA but rather to highlight important technical aspects, such as careful planning for certain tumor locations, of the procedure. Therefore, the title of the manuscript has been updated to Radiofrequency Ablation for the Local Treatment of Hepatocellular Carcinoma so that the reader is not led to believe significant technical discussion is provided. Introduction: from line 48-96, seems too length for this article. Readers who want to know the techniques and outcome are not interested to read this part. The original introduction was 614 words in length. We have reduced the length of the current introduction to 451 words to address this concern : 2 stage strategy with lipiodol. If I interpret this correctly, it should be transarterial lipiodol or TACE, then CT guided RFA. Or are they referring to US guided RFA afterwards? Please give an illustration case in figure. Thank you for pointing out the vagueness of this statement. This topic was significantly expanded to provide a clear description of the technique, and a figure was added to help illustrate the enhanced contrast resolution after lipiodol staining : why not mention Child Pugh class first? We appreciate this insightful comment as not all readers may be familiar with this classification system. Therefore, a reference to the use of the Child-Pugh classification system in pre-operative management of patients was added : RFA near the gall bladder. Mention the use of D5 solution or balloon. I think this is case report only. Most centres would use laparoscopic approach. May quote a reference to justify. We agree that in most cases of peri-gallbladder lesions that most centers, including ours, would use a laparoscopic approach. We have revised this section to emphasize our routine use of laparoscopic approach in difficult cases with a discussion of advanced techniques, such as artificial ascites, reserved for non-operative candidates. Furthermore, addition of a reference for the use of D5W to assist the percutaneous treatment of patients with tumors in difficult locations was added (25).

3 156: may mention the use of microwave ablation or auxiliary techniques for lesion near big vessels. eg. TACE + RFA or PEI + RFA. Thank you for pointing out the inadequate description of possible therapies for lesions near a large vessel. We have revised this section by expanding upon the use of TACE or PEI prior to RFA in order to achieve an adequate ablation zone. Furthermore, we mention that microwave ablation, through a different mechanism of coagulation, will avoid the heat-sink effect and provide an adequate ablation zone. 159:Unclear and confusing message here. BCLC reflect Milan's criteria. BCLC affects choice of patients for RFA, but Milan's criteria and choice of patient for RFA have some indirect relationship only. The description of the Milan criteria was removed from this section in order to address this comment. A relevant citation regarding guidelines for the percutaneous use of RFA was instead included. 180: A figure of incomplete ablation should be added : Sudden mentioning of PEI and MWA. Why not put it together in 232, 243. Thank you for noting the awkward appearance of the PEI and MWA. We have moved these discussions to the appropriate suggested locations. 251: Cryoablation. Again come out from nowhere and disappear. Mention of cryotherapy was removed. 446: Figure 1. A rim of hyperaemia is not routinely seen in the 1-month follow up CT. Actually, most do not have it. Thank you for pointing out this error on our part. The followup MRI was done about 36 hours after the ablation, not 4 weeks later. The contrast CT was done about 4 weeks later and shows lack of the peripheral rim. The figure legend was updated to reflect this new information. 449: Figure 2,3,4. Suggest to include number of patients in each histogram bar. The exact p- value should be given, which give a better idea to readers about the difference. The referenced figures were updated to include the exact p-values and total population studied for each comparison. In general, the authors use p0.05 in the text and figures. Most journals won't recommend this. Suggest more exact figure in p value. The exact p-values in the text and figures were included for proper reference.

4 Reviewer 2: This review is well written but some aspects should be considered by the Authors to make exhaustive their effort to outline the state-of-art HCC radiofrequency ablation: 1) the combined treatments (ethanol injection/rfa or TACE/RFA) should be mentioned (Yao-Jun Zhang et al Carcinoma Treated with Radiofrequency Ablation with or without Ethanol Injection: A Prospective Randomized Trial Radiology, 2007, Shibata et al Small Hepatocellular Carcinoma: Is Radiofrequency Ablation Combined with Transcatheter Arterial Chemoembolization More Effective than Radiofrequency Ablation Alone for Treatment? Radiology, 2009) Thank you for this important comment regarding the paucity of discussion of combined alcohol or TACE therapy with RFA, as well as providing us with references. We have added a subsection titled Combination Local Therapy with RFA to place emphasis on this combined therapy for HCC. Two references (36 and 39) in addition to those supplied are discussed in this subsection as well. 2) advanced technical aspects such as multiple needles approach (Sungmin Woo et al- and Medium-sized Hepatocellular Carcinomas: Monopolar Radiofrequency Ablation with a Multiple-Electrode Switching System Mid-term Results Radiology 2013) and early assessment of effectiveness of ablation with contrast enhanced US (Meloni et al Contrast enhanced ultrasound: Should it play a role in immediate evaluation of liver tumors following thermal ablation? Eur J Radiol. 2012) are lacking We appreciate the suggestion to add the newer Multiple-electrode Swtiching System to this review. The technique is novel and we do not have experience using it. This technique is discussed starting at line 149. We also discuss the immediate use after RFA of contrast-enhanced US (CEUS) to allow for more real-time decision making in regards to ablation zone, but caution the reader that the immediate use of CEUS reported significantly smaller ablation zones compared to images performed 24 hours later. 3) considering the international audience of the journal, the role of CEUS in the diagnosis of HCC in guidelines different from the AASLD should be mentioned (Bota S Liver Cancer Comparison of international guidelines for noninvasive diagnosis of hepatocellular carcinoma) We appreciate the reminder that the audience for this journal is international and agree that

5 comparison between major societal guidelines is appropriate. This article is referenced in the section of screening and diagnosis. However, discussion of this article is limited so that the opening paragraphs remain concise. 4) complications of RFA and methods to avoid them are not fully discussed (Mishal Mendiratta- Lal et al. Quality Initiatives: Strategies for Anticipating and Reducing Complications and Treatment Failures in Hepatic Radiofrequency Ablation. Radiographics 2010). The complications section of the manuscript has been enhanced with additional focus on postablation syndrome as well as recommendations to the reader for monitoring post-procedure.

6 Reviewer 3: In this manuscript, the authors summarized the technical issues and outcomes of RFA in patients with HCC. After careful reading of the manuscript, we felt that the organization of the manuscript should be ameliorated. And some spotlights concerning RFA were not taken into the scope of the review. Limitations that should be addressed are as follows. 1. Several sections of the literature review such as "RISK FACTORS AND SCREENING" seemed to be loosely connected with the topic of the present article. And several sections such as "STAGING AND TREATMENT ALGORITHMS" should be succinct. We appreciate this comment and have addressed them by reducing the word count in both sections. 2. The combination of RFA and other local therapeutic options such as TACE, PEI, microwave ablation is heatly discussed now. However, no relevant review and discussion is presented in the manuscript. Thank you for pointing out this deficiency in our manuscript. A separate section titled COMBINATION LOCAL THERAPY WITH RFA (line 192) was added to address the topic in more detail. 3. In Page 8, Line 159, the author quoted the Milan criteria. As RFA and liver transplantation are quite different in their underlying biological mechanisms, the Milan criteria might have littles hints for the patients assessment for RFA. We appreciate this comment regarding the discussion in our manuscript focused on Milan Criteria. We agree that the Milan criteria have only a loose relationship to RFA, and therefore, that discussion has been removed. 4. In page 13, Line 270, It may be hasty for the author to concluded that "the recurrence rate of HCC after RFA or surgical resection are not significantly different". As the authors themselves had quoted that the variance in recurrences rates between RFA and LR in this paragraph. We agree that data from prior studies is quite variable and that general conclusions regarding the rate of local recurrence after RFA should be avoided. The referenced sentence was revised to reflect this opinion. 5. As the title came as "Radiofrequency Ablation for the Management of Hepatocellular Carcinoma: Technical Aspects and Outcomes". Technical issues of RFA, such as the temperature, duration and the placement of the probe,etc., should be explained with more details. Please see response to the first comment from reviewer 1.