Emanuele Orlando

Staging systems of hepatocellular carcinoma: A review of literature

Hepatocellular carcinoma (HCC) is a major health problem with a high incidence and mortality all over the world. Natural history of HCC is severe and extremely variable, and prognostic factors influencing outcomes are incompletely defined. Over time, many staging and scoring systems have been proposed for the classification and prognosis of patients with HCC. Currently, the non-ideal predictive performance of existing prognostic systems is secondary to their inherent limitations, as well as to a non-universal reproducibility and transportability of the results in different populations. New serological and histological markers are still under evaluation with promising results, but they require further evaluation and external validation. The aim of this review is to highlight the main tools for assessing the prognosis of HCC and the main concerns, pitfalls and warnings regarding its staging systems currently in use.

Cyclosporine or infliximab as rescue therapy in severe refractory ulcerative colitis: early and long-term data from a retrospective observational study.

INTRODUCTION About 30-40% of patients with acute severe ulcerative colitis (UC) fail to respond to intensive intravenous (iv) corticosteroid treatment. Iv cyclosporine and infliximab are an effective rescue therapy in steroid-refractory UC patients but up to now it is still unclear which is the best therapeutic choice. METHODS We reviewed our series of severe steroid-refractory colitis admitted consecutively since 1994 comparing two historical cohort treated with iv cyclosporine (2 mg/kg) or iv infliximab (5 mg/kg). The main outcome was the colectomy rate at 3 months, 12 months and at the end of the follow-up. RESULTS A total of 65 patients were included: 35 in the cyclosporine group and 30 in the infliximab one. At 3 months the colectomy rate was 28.5% in the cyclosporine group and 17% in the infliximab group (p=0.25), while 48% versus 17% at 12 months (p=0.007, OR 4.7; 95% CI: 1.47-15.16). The 1-2-3 year cumulative colectomy rates were 48%, 54%, 57% in the cyclosporine group, and 17%, 23%, 27% in the infliximab group. At the end of the follow-up the colectomy rate was 60% versus 30% (p=0.04, HR 2.2; 95% CI: 1.11-4.86). High level of C reactive protein (p=0.04), extensive disease (p=0.01) and no azathioprine treatment (p<0.001) were related to the risk of colectomy. CONCLUSION This study, despite being retrospective, indicates that both cyclosporine and infliximab are effective in avoiding a colectomy in steroid-refractory UC patients. During the follow-up the risk of a colectomy is higher in patients treated with cyclosporine than with infliximab.

Metabolic Factors and Chronic Hepatitis C: A Complex Interplay

In the last years, several lines of evidence showed how metabolic factors may influence the natural history of patients with chronic hepatitis C. Chronic HCV infection is able to perturb the metabolic homeostasis of the host, in a context of complex interactions where pre-existent metabolic status and genetic background play an important role, allowing us to state that HCV infection is a systemic disease. In this review, we discuss the most recent lines of evidence on the main metabolic factors that are known to be associated with CHC, namely, insulin resistance/type 2 diabetes, steatosis, visceral obesity, atherosclerosis, vitamin D, menopause, fructose and coffee intake, lipoproteins, methylenetetrahydrofolate reductase status, and hyperuricaemia. In particular, we focus on the pathophysiological mechanisms underlying the correlation between HCV infection and metabolic disorders, the impact of metabolic factors on the progression of liver and non-liver-related diseases, and, on the contrary, the possible influence of chronic HCV infection on metabolic features. In this setting, the importance of a multifaceted evaluation of CHC patients and a prompt correction of modifiable metabolic risk factors should be emphasized.

Survival of patients with hepatocellular carcinoma (HCC) treated by percutaneous radio-frequency ablation (RFA) is affected by complete radiological response.

Background Radio-frequency ablation (RFA) has been employed in the treatment of Barcelona Clinic Liver Cancer (BCLC) early stage hepatocellular carcinoma (HCC) as curative treatments. Aim To assess the effectiveness and the safety of RFA in patients with early HCC and compensated cirrhosis. Methods A cohort of 151 consecutive patients with early stage HCC (122 Child-Pugh class A and 29 class B patients) treated with RFA were enrolled. Clinical, laboratory and radiological follow-up data were collected from the time of first RFA. A single lesion was observed in 113/151 (74.8%), two lesions in 32/151 (21.2%), and three lesions in 6/151 (4%) of patients. Results The overall survival rates were 94%, 80%, 64%, 49%, and 41% at 12, 24, 36, 48 and 60 months, respectively. Complete response (CR) at 1 month (p<0.0001) and serum albumin levels (p = 0.0004) were the only variables indipendently linked to survival by multivariate Cox model. By multivariate analysis, tumor size (p = 0.01) is the only variable associated with an increased likehood of CR. The proportion of major complications after treatment was 4%. Conclusions RFA is safe and effective for managing HCC with cirrhosis, especially for patients with HCC ≤3 cm and higher baseline albumin levels. Complete response after RFA significantly increases survival.

HCV/HBV coinfection: The dark side of DAAs treatment?

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/liv.13342 This article is protected by copyright. All rights reserved. Received Date : 29-Nov-2016 Revised Date : 06-Dec-2016 Accepted Date : 07-Dec-2016 Article type : Letter to the Editor Editor : Mario Mondelli

Tolerability profile of thiopurines in inflammatory bowel disease: a prospective experience

Abstract Objectives: The occurrence of thiopurine-related adverse events (AEs) may complicate the management of patients with inflammatory bowel disease (IBD). We aimed to evaluate the tolerability of thiopurines in a current IBD setting. Materials and methods: All consecutive patients who started a treatment with azathioprine (AZA) from January 2010 to March 2016 were entered in a prospectively maintained database, and the AEs which led to the permanent discontinuation of the drug were reported. Results: Two hundred and fifty three patients were included. Median total follow-up was 32 months (range: 0.2–75 months). At the end of the study, AZA was discontinued in 160 patients (63.2%). The main reason leading to drug withdrawal was the occurrence of AEs (109/160 patients [68.1%]; cumulative incidence among the entire cohort: 43.1%). Overall, the most frequent AEs leading to treatment withdrawal were nausea (31/253 patients, 12.3%) and subjective symptoms, i.e., poorly defined side effects such as fatigue, headache and muscle pain (20/253 patients, 7.9%). Among the 109 AZA-intolerant patients, a switch to 6-mercaptopurine (6-MP) was performed in 44 cases (40.4%). At the end of follow-up, 6-MP was discontinued in 35/44 patients (79.5%), mostly due to AEs (29/35 patients, 82.8%). Azathioprine-induced hepatic and pancreatic toxicity was associated with male gender (p = .01 and p = .03, respectively), and occurrence of nausea with Crohn’s disease (p = .04). Conclusions: Our real-life prospective cohort showed the higher cumulative incidence of thiopurine withdrawal due to AEs reported to date. Switching from AZA to 6-MP was often ineffective.

Letter: a prospective real life comparison of the efficacy of adalimumab vs. golimumab in moderate to severe ulcerative colitis

SIRS, Effectiveness of subcutaneous anti-tumour necrosis factor (TNF)-a antibodies, adalimumab (ADA) and golimumab (GOL), in the treatment of moderate to severe ulcerative colitis (UC), was shown in two randomised trials. 2 However, to our knowledge, no direct comparison of the two drugs has been published, while network meta-analyses have reported variable results. We agree with the results of the meta-analysis published by Stidham et al., where infliximab (IFX), ADA and GOL were all effective in UC. We report our experience on the efficacy of ADA and GOL in patients with moderate to severe UC. From June 2015 until April 2016, we prospectively evaluated 40 patients: 21 treated with ADA at the induction dosage of 160/80 mg followed by 40 mg every other week, 19 treated with GOL at the induction dosage of 200/ 100 mg followed by 50 or 100 mg, according to body weight, every 4 weeks. Patient characteristics, Mayo score and main results are shown in Table 1. Nineteen patients were na€ıve to anti-TNFa treatment: fourteen and five in the ADA and GOL group, respectively. Twenty-one patients had been previously treated with IFX: eleven discontinued for adverse events, eight for no response or loss of response, and two for previous remission. At 8 weeks, clinical remission was achieved in 15/40 patients (37.5%): 9/19 (47.3%) na€ıve and 6/21 (28.5%)

P387 The addition of an immunosuppressant is an effective optimization strategy after loss of response to anti-TNF-alpha monotherapy in patients with inflammatory bowel disease: a two-year experience

Crohn’s disease (CD), and that 6-thioguanine nucleotide (TGN) levels ≥125 pmol/8×108 RBC positively influence IFX pharmacokinetics. We aim to assess clinical outcomes after induction and during maintenance in CD patients treated with IFX and a thiopurine with respect to TGN and IFX levels. Methods: CD patients commenced on IFX between 2010–15 with or without concomitant thiopurines were retrospectively identified. “Response” to induction (CRP <5mg/L and absence of activity on physician global assessment) or “non response” (lack of clinical improvement during induction or flare requiring CD therapy adjustment or surgery during first 6 months) were assessed at week 14. Maintenance outcomes were assessed in 6-month semesters and classed as “response”, “flare” or “failure” (IFX cessation due to active disease or intolerance). TGN and IFX trough levels were recorded during induction and maintenance. Results: Of 89 patients (49 male, mean age 35y, range 18–61), combination therapy (n=73) had a higher response than IFX monotherapy (n=16) on induction (78% vs 50%, p=0.02). Median TGN was similar between responders and non-responders (314 vs 254, p=0.12), with TGN ≥125 patients more likely to respond (76% vs 47%, p=0.018). On multivariable analysis, TGN ≥125 was associated with response (OR 5.7; 95% CI: 1.6–20.1; p=0.006). Mean time to IFX failure was 26 months for monotherapy vs 53 months for combination therapy (p=0.55); a significant difference was observed when re-stratified by TGN ≥125, p=0.043 (Fig. 1).

Could JC virus provoke metastasis in colon cancer

AIM To evaluate the prevalence of John Cunningham virus (JC virus) in a small cohort of patients with colon cancer and to assess its presence in hepatic metastasis. METHODS Nineteen consecutive patients with histologically diagnosed colon cancer were included in our study, together with ten subjects affected by histologically and serologically diagnosed hepatitis C virus infection. In the patients included in the colon cancer group, JC virus was searched for in the surgical specimen; in the control group, JC virus was searched for in the hepatic biopsy. The difference in the prevalence of JC virus in the hepatic biopsy between the two groups was assessed through the χ(2) test. RESULTS Four out of 19 patients with colon cancer had a positive polymerase chain reaction (PCR) test for JC virus, and four had liver metastasis. Among the patients with liver metastasis, three out of four had a positive PCR test for JC virus in the surgical specimen and in the liver biopsy; the only patient with liver metastasis with a negative test for JC virus also presented a negative test for JC virus in the surgical specimen. In the control group of patients with hepatitis C infection, none of the ten patients presented JC virus infection in the hepatic biopsy. The difference between the two groups regarding JC virus infection was statistically significant (χ(2) = 9.55, P = 0.002). CONCLUSION JC virus may play a broader role than previously thought, and may be mechanistically involved in the late stages of these tumors.

Mycophenolate mofetil is a valid option in patients with inflammatory bowel disease resistant to TNF-α inhibitors and conventional immunosuppressants

BACKGROUND Few studies investigated the role of mycophenolate mofetil in inflammatory bowel disease, and none of them had specifically focused on patients with previous multiple intolerances and/or nonresponses to conventional immunosuppressants and biologics. AIMS To evaluate clinical benefit and tolerability profile of mycophenolate mofetil in patients with inflammatory bowel disease and limited treatment options. METHODS All consecutive patients with previous multiple intolerances and/or nonresponses to immunosuppressants and biologics who started an off-label treatment with mycophenolate mofetil from January 2014 to February 2016 were entered in a prospectively maintained database. RESULTS Twenty-four patients were included. Four weeks after initiation of mycophenolate mofetil therapy, a steroid-free remission was achieved in 4 patients (16.7%), while a clinical response in 13 (54.1%). At the end of follow-up, 12 patients (50.0%) remained on mycophenolate mofetil. Six achieved and maintained steroid-free remission throughout the study period (25.0%), and a further 6 patients (25.0%) achieved a clinical response with complete discontinuation of steroids. Twelve patients (50.0%) were considered as treatment failure, and five of them underwent surgery. CONCLUSIONS This is the first experience reporting a clinical benefit and tolerability of mycophenolate mofetil in patients with inflammatory bowel disease and multiple previous failures to other immunosuppressants and/or biologics.