Title:Evaluation of 11C Acetate and 18F-FDG PET/CT in Mouse Multidrug Resistance Gene-2 Deficient Mouse Model of Hepatocellular Carcinoma

Transcription

1 Author's response to reviews Title:Evaluation of 11C Acetate and 18F-FDG PET/CT in Mouse Multidrug Resistance Gene-2 Deficient Mouse Model of Hepatocellular Carcinoma Authors: Paul R Teritto (pterrito@iupui.edu) Mary A Maluccio (mmalucci@iupui.edu) Amanda A Riley (amariley@iupui.edu) Brian P McCarthy (brpmccar@iupui.edu) James W Fletcher (jwfletch@iupui.edu) Mark A Tann (matann@iupui.edu) Romil Saxena (rsaxena@iu.edu) Nicholas J Skill (nskill@iupui.edu) Version:4Date:22 September 2014 Author's response to reviews: see over

2 September 22th, 2014 To Whom It May Concern: Please accept our revised manuscript entitled Evaluation of 11 C Acetate and 18 F-FDG PET/CT in Mouse Multidrug Resistance Gene-2 Deficient Mouse Model of Hepatocellular Carcinoma in consideration for publication in the journal of Cancer Imaging. The manuscript has been modified in line with the critique and comments made by the two reviewing editors. We hope these edits are satisfactory and raises our manuscript to acceptable standards for publication. Yours Sincerely Nicholas J Skill

3 Reviewer's report Title: Evaluation of 11C Acetate and 18F-FDG PET/CT in Mouse Multidrug Resistance Gene-2 Deficient Mouse Model of Hepatocellular Carcinoma Version:3Date:25 August 2014 Reviewer number:1 Reviewer's report: The paper reports on a preclinical study aiming of evaluating imaging biomarkers for HCC. A small clinical study on humans is reported as translation of the preclinical experience. Major compulsory revisions: 1-The number of animals studied should be indicated in the abstract and in the text. Abstract and Methods edited. 2-Epidemiology data for Asia, South America and Europe, not only for North America, should be reported. When not available, it should be noted. Two new references which report the epidemiology of HCC worldwide added to the discussion. 3-Image analyses paragraph can be safely shortened, deleting formulas Formulas removed and reference added. 4-It should be better specified if mice where anaesthetised during FDG imaging Methods section edited 5-Some wording from the introduction is repeated in the discussion. This should be corrected Introduction has been edited. 6-Discussion should be more focused on the usefulness of results from this study. Discussion has been edited Level of interest: An article whose findings are important to those with closely related research interests Quality of written English: Acceptable Statistical review: No, the manuscript does not need to be seen by a statistician.

4 Reviewer's report Title: Evaluation of 11C Acetate and 18F-FDG PET/CT in Mouse Multidrug Resistance Gene-2 Deficient Mouse Model of Hepatocellular Carcinoma Version:3Date:26 August 2014 Reviewer number:2 Reviewer's report: Major compulsory revision: Methods: A table with number and type of mice including the time to HCC development, the histology and the size of the tumors is recommended. Table added. The inclusion criteria of the patients are missing. Were patients examined only based on clinical routine indications only (rising AFP, indeterminate CT and/(or MRI findings)? Inclusion criteria added. The description of LPA measurements is missing LPA MS method added. How was the 11C-acetate uptake quantified in mice experiments and in patient studies? Were measurements performed only of the whole liver or separately of normal tissue and tumor? Separate measurements are important to estimate uptake differences of normal liver and tumor. In this study 11C acetate uptake was limited to the liver. Organ uptake of 11C acetate uptake has been shown by Selzer et al The methods section has been edited. Results: A correlation of radiotracer uptake and serum/tissue parameters is missing No correlates are available. Separate mice were used for 11C acetate imaging and serum/tissue analysis. The methods section has bee nedited to clarify this. Detailed analyses of patient data are missing. How were the diagnoses verified or confirmed? Follow-up examinations or histology? The results have been supplemented to the extent that data can be provided congruent with our IRB exemption for research data. Concerning the paragraph of serum LPA: do not include discussion and reference in the results section and shift it to the discussion section.

5 Discussion has been edited Fig 2-5: It would be interesting to see not only the mean of the measured parameters, but rather their individual changes over time. We agree. However, this work is internally funded and the imaging is expensive. We have a grant pending to conduct a time course study that is scheduled for review in December. Discussion: Please discuss the advantage of 11C-acetate PET/CT over LPA serum measurements, particularly in case that the 11C-acetate uptake of only the whole liver is quantified? PET contains spatial information, and in a patient population which has non-diffuse disease, this would allow for Y90 thearaspheres to be deployed as treatment of HCC. In a mouse model with more uniform distribution this does not apply. LPA has a limit of detection in the nmol/ml range but PET has sensitivity in the fmol/ml range. The discussion has been edited. The conclusion that 11C-acetate PET/CT is well suited study new chemotherapeutics in murine models of HCC or even in clinical studies is not substantiated by the results. For this measurements of mice undergoing treatment have to be performed. Agreed. Discussion edited. Level of interest:an article whose findings are important to those with closely related research interests Quality of written English:Acceptable Statistical review:no, the manuscript does not need to be seen by a statistician.