Invited Editorials agent (namely doxorubicin) varies hugely from one centre and one interventional radiologist to another as clearly pointed out in the article of Marelli et al.3 7 years ago. In 2008, Llovet et al. concluded that there was an urgent need for high-quality trials in HCC, and that specific phase I studies in Child–Pugh A patients with cirrhosis were recommended to estimate the exact dose, toxicity and risk of liver-related adverse events, as such data are not captured by phase I studies that include patients with a large variety of cancers.4 Following these recommendations and after promising pre-clinical data,5 we conducted the IDASPHERE phase I trial. Besides determining the interest of 10-mg MTD of idarubicin-loaded beads, the key point of our study was also to present detailed information on toxicity and the pharmacokinetic profile of the treatment as well as quality of life in these HCC patients. As mentioned above, the next step will be to evaluate efficacy of, and tolerance to, idarubicin-loaded beads through phase II/III randomised trials. To this end, the IDASPHERE II trial will start soon. This multicentre phase II trial promoted by the Federation Francophone
Editorial: probiotics in NASH – more studies are needed J. P. Ong* & Z. M. Younossi† *Section of Gastroenterology, Department of Medicine, Philippine General Hospital, University of the Philippines Manila, Manila, Philippines. † Claude Moore Health Education and Research Building, Betty and Guy Beatty Center for Integrated Research, Falls Church, VA, USA. E-mail: [email protected] doi:10.1111/apt.12812
The manipulation of gut microbiota to treat liver disease is an area of active clinical investigation.1 Alisi et al. recently published the results of their study on the use of the probiotic mixture, VSL#3, on non-alcoholic steatohepatitis (NASH) in children.2 They found that VSL#3 led to significant improvements in fatty liver severity assessed by ultrasound in obese children with biopsy proven NASH. In addition, the authors found that the patients who received VSL#3 had a significant decrease in their BMI, while those on placebo did not. They proposed that the use of VSL#3 led to the weight loss through correction of dysbiosis. Aliment Pharmacol Ther 2014; 40: 208-212 ª 2014 John Wiley & Sons Ltd
de Cancerologie Digestive (FFCD-1307) will evaluate as the primary objective the response rate using mRECIST criteria at 6 months in unresectable HCC patients treated with TACE using idarubicin-loaded beads.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Lee GH, Lim SG. Editorial: IDASPHERE phase I trial for chemoembolisation of HCC. Aliment Pharmacol Ther 2014; 40: 209–10. 2. Boulin M, Hillon P, Cercueil JP, et al. Idarubicin-loaded beads for chemoembolisation of hepatocellular carcinoma: results of the IDASPHERE phase I trial. Aliment Pharmacol Ther 2014; 39: 1301–13. 3. Marelli L, Stigliano R, Triantos C, et al. Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomised studies. Cardiovasc Intervent Radiol 2007; 30: 6–25. 4. Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. JNCI 2008; 100: 698– 711. 5. Boulin M, Guiu S, Chauffert B, et al. Screening of anticancer drugs for chemoembolisation of hepatocellular carcinoma. Anticancer Drugs 2011; 22: 741–8.
It is worth noting that in a small pilot study of VSL#3 use in four adults, Solga et al. did not find any changes in clinical parameters, and found increased hepatic fat on proton magnetic resonance spectroscopy after 4 months, which improved to near baseline after a washout of 3 months.3 Moreover, there were no differences in the BMI between the treatment and control arms in another trial of probiotics that included 20 obese children with non-alcoholic fatty liver disease (NAFLD) and in a meta-analysis of clinical trials of probiotics use in NAFLD.4, 5 The differences in the results among the various trials may be accounted for by the small sample sizes or by differences in the probiotics preparations, the dose of the probiotics, the duration of follow-up or treatment endpoints. More studies need to be done with particular attention to sample size and potential confounding variables such as concomitant use of medications (e.g. prebiotics) and lifestyle intervention strategies.6, 7 Characterisation of the gut microbiota as well as use of a washout follow-up period and histological outcome measures should be considered. Nevertheless. the results of the study by Alisi et al. add to the growing body of evidence that lend support to the use of probiotics for the treatment of obesity-related NAFLD. Probiotics may find particular use in 211
Invited Editorials patients who have been unsuccessful with lifestyle intervention strategies.
ACKNOWLEDGEMENT Declaration of personal interests: Zobair Younossi: Consultant for Coneatus, Enterome, Gilead; advisory Board for Vertex, Janssen, Salix. Declaration of funding interests: None.
3.
4.
5. 6.
REFERENCES 1. Chassaing B, Etienne-Mesmin L, Gewirtz AT. Microbiota-liver axis in hepatic disease. Hepatology 2014; 59: 328–39. 2. Alisi A, Bedogni G, Baviera G, et al. Randomised clinical trial: the beneficial effects of VSL#3 in obese children
Editorial: probiotics in NASH – more studies are needed; authors’ reply A. Alisi & V. Nobili Hepato-Metabolic Disease Unit and Liver Research Unit, “Bambino Gesu” Children’s Hospital, IRCCS, Rome, Italy. E-mail: [email protected] doi:10.1111/apt.12816
We appreciate Dr Ong and Younossi for their interest in, and valuable comment on, our recent article.1 With our results, we provide the first evidence that the VSL#3 probiotic mixture may improve BMI and fatty liver on ultrasound, enhancing the enthusiasm about the use of this combination as a long-term therapeutic strategy for obesity-related non-alcoholic steatohepatitis (NASH), at least in children.2 Regarding the discrepancies observed in our study with respect to those previously performed either in adults or children with non-alcoholic fatty liver disease, several factors should be considered including diagnostic accuracy in detecting NASH, sample size, primary and secondary endpoints, and overall differences in the variety and amount of bio-organisms contained in the probiotics mixture.3, 4 We believe that high-doses of VSL#3 may exert a very good response to therapy, while lower doses may have opposite or mixed results. In fact, if adult patients in the Solga study received approximately 0.01%/kg of the
212
7.
with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2014; 39: 1276–85. Solga SF, Buckley G, Clark JM, Horska A, Diehl AM. The effect of a probiotic on hepatic steatosis. J Clin Gastroenterol 2008; 42: 1117–9. Vajro P, Mandato C, Licenziati MR, et al. Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J Pediatr Gastroenterol Nutr 2011; 52: 740–3. Ma Y-Y. Effects of probiotics on nonalcoholic fatty liver disease: a meta-analysis. World J Gastroenterol 2013; 19: 6911. Nobili V, Manco M, Devito R, et al. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology 2008; 48: 119–28. Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 2011; 54: 344–53.
VSL#3 contained in one sachet, our children received 10 times more (0.1%/kg) of the same mix.2, 5 Thus, it is conceivable that the dose of VSL#3 has been particularly crucial to determine the beneficial effects observed in our patients. In addition, as highlighted by Ong and Younossi in their editorial, a wash-out follow-up period and histology assessment are necessary to corroborate the early improvement observed in our cohort.1, 2 The metabolomic analysis of these patients should also be able to confirm our published findings.
ACKNOWLEDGEMENTS The authors’ declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES 1. Ong JP, Younossi ZM. Editorial: probiotics in NASH – more studies are needed. Aliment Pharmacol Ther 2014; 40: 211–2. 2. Alisi A, Bedogni G, Baviera G, et al. Randomised clinical trial: the beneficial effects of VSL#3 in obese children with nonalcoholic steatohepatitis. Aliment Pharmacol Ther 2014; 39: 1276–85. 3. Vajro P, Mandato C, Licenziati MR, et al. Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J Pediatr Gastroenterol Nutr 2011; 52: 740–3. 4. Loguercio C, Federico A, Tuccillo C, et al. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol 2005; 39: 540–3. 5. Solga SF, Buckley G, Clark JM, Horska A, Diehl AM. The effect of a probiotics on hepatic steatosis. J Clin Gastroenterol 2008; 42: 1117–9.
Aliment Pharmacol Ther 2014; 40: 208-212 ª 2014 John Wiley & Sons Ltd
Editorial: probiotics in NASH – more studies are needed J. P. Ong* & Z. M. Younossi† *Section of Gastroenterology, Department of Medicine, Philippine General Hospital, University of the Philippines Manila, Manila, Philippines. † Claude Moore Health Education and Research Building, Betty and Guy Beatty Center for Integrated Research, Falls Church, VA, USA. E-mail: [email protected] doi:10.1111/apt.12812
The manipulation of gut microbiota to treat liver disease is an area of active clinical investigation.1 Alisi et al. recently published the results of their study on the use of the probiotic mixture, VSL#3, on non-alcoholic steatohepatitis (NASH) in children.2 They found that VSL#3 led to significant improvements in fatty liver severity assessed by ultrasound in obese children with biopsy proven NASH. In addition, the authors found that the patients who received VSL#3 had a significant decrease in their BMI, while those on placebo did not. They proposed that the use of VSL#3 led to the weight loss through correction of dysbiosis. Aliment Pharmacol Ther 2014; 40: 208-212 ª 2014 John Wiley & Sons Ltd
de Cancerologie Digestive (FFCD-1307) will evaluate as the primary objective the response rate using mRECIST criteria at 6 months in unresectable HCC patients treated with TACE using idarubicin-loaded beads.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Lee GH, Lim SG. Editorial: IDASPHERE phase I trial for chemoembolisation of HCC. Aliment Pharmacol Ther 2014; 40: 209–10. 2. Boulin M, Hillon P, Cercueil JP, et al. Idarubicin-loaded beads for chemoembolisation of hepatocellular carcinoma: results of the IDASPHERE phase I trial. Aliment Pharmacol Ther 2014; 39: 1301–13. 3. Marelli L, Stigliano R, Triantos C, et al. Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomised studies. Cardiovasc Intervent Radiol 2007; 30: 6–25. 4. Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. JNCI 2008; 100: 698– 711. 5. Boulin M, Guiu S, Chauffert B, et al. Screening of anticancer drugs for chemoembolisation of hepatocellular carcinoma. Anticancer Drugs 2011; 22: 741–8.
It is worth noting that in a small pilot study of VSL#3 use in four adults, Solga et al. did not find any changes in clinical parameters, and found increased hepatic fat on proton magnetic resonance spectroscopy after 4 months, which improved to near baseline after a washout of 3 months.3 Moreover, there were no differences in the BMI between the treatment and control arms in another trial of probiotics that included 20 obese children with non-alcoholic fatty liver disease (NAFLD) and in a meta-analysis of clinical trials of probiotics use in NAFLD.4, 5 The differences in the results among the various trials may be accounted for by the small sample sizes or by differences in the probiotics preparations, the dose of the probiotics, the duration of follow-up or treatment endpoints. More studies need to be done with particular attention to sample size and potential confounding variables such as concomitant use of medications (e.g. prebiotics) and lifestyle intervention strategies.6, 7 Characterisation of the gut microbiota as well as use of a washout follow-up period and histological outcome measures should be considered. Nevertheless. the results of the study by Alisi et al. add to the growing body of evidence that lend support to the use of probiotics for the treatment of obesity-related NAFLD. Probiotics may find particular use in 211
Invited Editorials patients who have been unsuccessful with lifestyle intervention strategies.
ACKNOWLEDGEMENT Declaration of personal interests: Zobair Younossi: Consultant for Coneatus, Enterome, Gilead; advisory Board for Vertex, Janssen, Salix. Declaration of funding interests: None.
3.
4.
5. 6.
REFERENCES 1. Chassaing B, Etienne-Mesmin L, Gewirtz AT. Microbiota-liver axis in hepatic disease. Hepatology 2014; 59: 328–39. 2. Alisi A, Bedogni G, Baviera G, et al. Randomised clinical trial: the beneficial effects of VSL#3 in obese children
Editorial: probiotics in NASH – more studies are needed; authors’ reply A. Alisi & V. Nobili Hepato-Metabolic Disease Unit and Liver Research Unit, “Bambino Gesu” Children’s Hospital, IRCCS, Rome, Italy. E-mail: [email protected] doi:10.1111/apt.12816
We appreciate Dr Ong and Younossi for their interest in, and valuable comment on, our recent article.1 With our results, we provide the first evidence that the VSL#3 probiotic mixture may improve BMI and fatty liver on ultrasound, enhancing the enthusiasm about the use of this combination as a long-term therapeutic strategy for obesity-related non-alcoholic steatohepatitis (NASH), at least in children.2 Regarding the discrepancies observed in our study with respect to those previously performed either in adults or children with non-alcoholic fatty liver disease, several factors should be considered including diagnostic accuracy in detecting NASH, sample size, primary and secondary endpoints, and overall differences in the variety and amount of bio-organisms contained in the probiotics mixture.3, 4 We believe that high-doses of VSL#3 may exert a very good response to therapy, while lower doses may have opposite or mixed results. In fact, if adult patients in the Solga study received approximately 0.01%/kg of the
212
7.
with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2014; 39: 1276–85. Solga SF, Buckley G, Clark JM, Horska A, Diehl AM. The effect of a probiotic on hepatic steatosis. J Clin Gastroenterol 2008; 42: 1117–9. Vajro P, Mandato C, Licenziati MR, et al. Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J Pediatr Gastroenterol Nutr 2011; 52: 740–3. Ma Y-Y. Effects of probiotics on nonalcoholic fatty liver disease: a meta-analysis. World J Gastroenterol 2013; 19: 6911. Nobili V, Manco M, Devito R, et al. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology 2008; 48: 119–28. Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 2011; 54: 344–53.
VSL#3 contained in one sachet, our children received 10 times more (0.1%/kg) of the same mix.2, 5 Thus, it is conceivable that the dose of VSL#3 has been particularly crucial to determine the beneficial effects observed in our patients. In addition, as highlighted by Ong and Younossi in their editorial, a wash-out follow-up period and histology assessment are necessary to corroborate the early improvement observed in our cohort.1, 2 The metabolomic analysis of these patients should also be able to confirm our published findings.
ACKNOWLEDGEMENTS The authors’ declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES 1. Ong JP, Younossi ZM. Editorial: probiotics in NASH – more studies are needed. Aliment Pharmacol Ther 2014; 40: 211–2. 2. Alisi A, Bedogni G, Baviera G, et al. Randomised clinical trial: the beneficial effects of VSL#3 in obese children with nonalcoholic steatohepatitis. Aliment Pharmacol Ther 2014; 39: 1276–85. 3. Vajro P, Mandato C, Licenziati MR, et al. Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J Pediatr Gastroenterol Nutr 2011; 52: 740–3. 4. Loguercio C, Federico A, Tuccillo C, et al. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol 2005; 39: 540–3. 5. Solga SF, Buckley G, Clark JM, Horska A, Diehl AM. The effect of a probiotics on hepatic steatosis. J Clin Gastroenterol 2008; 42: 1117–9.
Aliment Pharmacol Ther 2014; 40: 208-212 ª 2014 John Wiley & Sons Ltd
