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September 27, 2016 Ioannis Koutroubakis MD PhD Editor-in-Chief; Annals of Gastroenterology Associate Professor of Medicine University Hospital Heraklion Department of Gastroenterology P.O BOX 1352 , 71110 Heraklion, Crete, Greece e-mail:[email protected] Tel: + 30.2810392254 fax: +30.2810542085 Re: Annals of Gastroenterology, manuscript #2972 Dear Dr. Koutroubakis, Kindly find attached our revised manuscript entitled “Viral hepatitis status does not affect survival in hepatocellular carcinoma” for consideration of publication in Annals of Gastroenterology. The manuscript has been edited based on the comments of the reviewers and following is the letter of itemized responses. Thank you for considering our revised manuscript Sincerely, Eyas Alkhalili, MD Response to reviewers. Re: Annals of Gastroenterology, manuscript #2972 Reviewer A: The present study tries to address the question of the impact of viral etiology on the prognosis of patients with HCC , analyzed as an independent factor . It is however, limited as an one center retrospective study with 233 patients with Viral (HBV or HCV positive) etiology of HCC, and 133 HCC cases virus negative whose main etiology is alcohol induced chronic liver disease or NASH. Although sample size is rather small to produce firm conclusions, one of the important strengths of this study in comparison to previous studies, is the inclusion of one third of the cases of non viral etiology HCC. On multivariate analysis , disease stage and Child-Pugh class were independent factors affecting survival, but viral factor was not. Patients with V-HCC presented with more advanced cirrhosis and had a lower likelihood to undergo hepatectomy. The study although has limitations such as particular ethnic groups in new Mexico and the fact that it did not accounted for difference in surveillance patterns between etiologies of HCC, (viral cirrhosis has more solid surveillance in general clinical practice ) puts into consideration the important question of adjuvant antiviral treatment possible effect on survival in V-HCC ,without a counterpart available for NBNC-HCC. Thank you for your encouraging review. We have no additions or comments. Reviewer B: 1) The survival in Fig 2 (according to disease stage) should be changed in stage two disease. The x-axis (months of survival) should change according to the other three stages so the comparisons are straigtforward. Moreover the median survival of the four stages should be reported along with the overall median survival at the appropriate paragraph at the results section. - We have edited figure 2 and reloaded the new version to the revised manuscript. The new paragraph now reads as follows: “No differences were found for stage-specific median survivals for stage I (36 months in V-HCC vs. 29 months NBNC-HCC), stage II (13 vs 14 months), stage III (6 vs. 7 months), and stage IV (5 vs 6 months) (Figure 2).” 2) The authors should include any previous antiviral treatment the viral cases have received. This might have influenced the result. If the number of treated with antivirals cirrhotics is relatively large this parameter should be included in the multivariate analysis. - The first agents to treat viral hepatitis agents (Boceprevir and Telaprevir) were only approved by the FDA in 2011 and as such the vast majority of our patients were not on antiviral therapy in the study period (2000-2014). The effect of these treatments would have an impact on patients’ liver disease, however, the vast majority of patients diagnosed and treated prior to approval of these medications. Moreover, this data is not complete in our data and not available to us as some patients were referred to our cancer institution for treatment of their HCC while treatment of their underlying liver disease and hepatitis were performed elsewhere. 3) The authors should comment on the fact that the vast majority of their viral cirrhotics are HCV cirrhosis who may have a better survival than HBV. In our recent paper (World J Hepatology 6504-51,2014) we reported that HBV cirrhotics have twice the risk of death compared to HCV cirrhotics. - This has been edited and addressed in the discussion section. Manuscript now reads: “ Another study by the ILCG demonstrated a difference in survival in advanced HCC between different types of hepatitis; as patients with hepatitis B had better survival than those associated with hepatitis C (HR 1.5, 95% CI 1-2.29, p=0.048) (23). This has not been consistent in the literature, however. Samonakis et al. found contradictory results with Hepatitis B being associated with twice the risk of death of HCV patients (24). The majority of our V-HCC patients had hepatitis C which makes this patient group overrepresented when compared to hepatitis B and the results group might be more reflective of these patients’ prognosis.” 4) TNM classification may not be the best way of staging in HCC. Certainly the Barcelona or the Italian classification are prognostically more accurate,although even with the TNM system,stage is a significant prognostic factor in their study. They should however comment in the discussion that an other classification might have strengthened the significance. - The discussion has been revised. The other staging systems were mentioned in the discussion section and while these may be more prognostic and incorporate the stage of cirrhosis into the classification, we use the TNM system which despite its limitations has shown to be strongly predictive of survival in our survival and multivariate analysis. Discussion now reads as follows: “We used the TNM staging system and found similar stage distribution between the two groups. Although the other staging systems account for cirrhosis while the TNM does not, the TNM staging system was an independent factor of prognosis and it’s the preferred staging system at our institution.” Thank you for considering our revised manuscript. Editor's comments: 1. A summary box according to Journal's guidelines (What is already known about this subject: 3-4 bullet points What are the new findings: 3-4 bul points) should be added - These has been added to the manuscript. 2. All abbreviations used in each table should be explained at the bottom - These have been added to the tables. 3. The references should follow the Journal's style - These have been edited appropriately. Thank you for considering our revised manuscript.