Genetic Biomarkers of Sorafenib Response in Patients with Hepatocellular Carcinoma.

The identification of biomarkers for predicting inter-individual sorafenib response variability could allow hepatocellular carcinoma (HCC) patient stratification. SNPs in angiogenesis- and drug absorption, distribution, metabolism, and excretion (ADME)-related genes were evaluated to identify new potential predictive biomarkers of sorafenib response in HCC patients. Five known SNPs in angiogenesis-related genes, including VEGF-A, VEGF-C, HIF-1a, ANGPT2, and NOS3, were investigated in 34 HCC patients (9 sorafenib responders and 25 non-responders). A subgroup of 23 patients was genotyped for SNPs in ADME genes. A machine learning classifier method was used to discover classification rules for our dataset. We found that only the VEGF-A (rs2010963) C allele and CC genotype were significantly associated with sorafenib response. ADME-related gene analysis identified 10 polymorphic variants in ADH1A (rs6811453), ADH6 (rs10008281), SULT1A2/CCDC101 (rs11401), CYP26A1 (rs7905939), DPYD (rs2297595 and rs1801265), FMO2 (rs2020863), and SLC22A14 (rs149738, rs171248, and rs183574) significantly associated with sorafenib response. We have identified a genetic signature of predictive response that could permit non-responder/responder patient stratification. Angiogenesis- and ADME-related genes correlation was confirmed by cumulative genetic risk score and network and pathway enrichment analysis. Our findings provide a proof of concept that needs further validation in follow-up studies for HCC patient stratification for sorafenib prescription.

Sarcopenia increases mortality risk in liver transplantation: a systematic review and meta-analysis.

INTRODUCTION: Liver transplantation is an efficacious treatment option for those with liver cirrhosis. However, the prognostic role of sarcopenia in these patients is unknown. Given this background, we conducted a systematic review and meta-analysis of the impact of sarcopenia on mortality in patients listed, evaluated and undergoing liver transplantation. EVIDENCE ACQUISITION: Several databases were searched from the inception to December 2022 for observational studies regarding sarcopenia in liver transplant and mortality. We calculated the risk of mortality in sarcopenia vs. no sarcopenia using the most adjusted estimate available and summarizing the data as risk ratios (RRs) with their 95% confidence intervals (CIs). A random-effect model was considered for all analyses. EVIDENCE SYNTHESIS: Among 1135 studies initially considered, 33 articles were included for a total of 12,137 patients (mean age: 55.3 years; 39.4% females). Over a median of 2.6 years and after adjusting for a median of 3 covariates, sarcopenia increased the risk of mortality approximately 2-fold (RR: 2.01; 95% CI: 1.70-2.36). After accounting for publication bias, the re-calculated RR was 1.75 (95% CI: 1.49-2.06). The quality of the studies was generally low, as determined by the Newcastle Ottawa Scale. CONCLUSIONS: Sarcopenia was significantly linked with an increased risk of mortality in patients listed, evaluated, and undergoing a liver transplantation, indicating the need of interventional studies in this special population with the main aim to reverse this potential reversible condition and decrease mortality risk.

Impact of Actively Offering Influenza Vaccination to Frail People during Hospitalisation: A Pilot Study in Italy.

Despite the worldwide recommendations for influenza immunisation, vaccination coverage for patients exposed to the highest risk of severe complications is still far from the optimal target. The need to take advantage of alternative methods to provide vaccination is essential. This study presents a hospital-based strategy which offers influenza vaccination to inpatients at discharge. This study was conducted during the 2022-2023 influenza season at the University Hospital of Palermo. A questionnaire was administered to identify the determinants for the acceptance of influenza vaccination in the frail population. Overall, 248 hospitalised patients were enrolled, of which 56.1% were female and 52.0% were over 65 years of age. The proportion of patients vaccinated against influenza during hospitalisation was 62.5%, an increase of 16% in influenza vaccination uptake among frail people in comparison with the previous influenza season (46.8% vaccinated during the 2021-22 influenza season). Factors significantly associated with vaccination acceptance were the following: to have received influenza vaccine advice from hospital healthcare workers (OR = 3.57, p = 0.001), to have been previously vaccinated for influenza (OR = 3.16 p = 0.005), and to have had a low level of education (OR = 3.56, p = 0.014). This study showed that offering influenza vaccination to hospitalised patients could be an effective strategy to increase vaccination coverage in the most vulnerable population, and these findings could be useful for planning and improving future influenza vaccination campaigns.

The Addition of an Immunosuppressant After Loss of Response to Anti-TNFα Monotherapy in Inflammatory Bowel Disease: A 2-Year Study.

Background: The addition of an immunosuppressant (IM) after loss of response to anti-TNFα monotherapy is an emerging strategy of therapeutic optimization in patients with inflammatory bowel disease (IBD). However, few clinical data have been reported to date. We aimed to evaluate the efficacy and safety of this selective combination therapy in patients with IBD. Methods: All consecutive patients with loss of response to anti-TNFα monotherapy despite an intensive dose optimization who added an IM from October 2014 to October 2016 were entered into a prospective database. Results: Among 630 patients treated with anti-TNFα agents during the study period, 46 (7.3%) added an IM. A total of 31 patients (67.4%) were treated with an intravenous anti-TNFα (infliximab, as originator or biosimilar), while 15 (32.6%) were treated with a subcutaneous anti-TNFα agent (10 adalimumab and 5 golimumab). The mean duration of follow-up was 12.8 ± 7.3 months. Twenty-one patients (45.7%) remained on combination therapy at the end of follow-up: 15 (32.6%) maintained a steroid-free remission, and 6 (13.0%) achieved a clinical response. In patients who experienced treatment success, the median value of C-reactive protein decreased from baseline to the end of follow-up (13.2 vs 3.0, P = 0.01; normal values <5 mg/L). Adverse events leading to treatment discontinuation were reported in 8 out of 46 patients (17.4%). Conclusions: In the largest cohort on this argument reported to date, the addition of an IM was an effective and safe optimization strategy after loss of response to anti-TNFα monotherapy. Low doses of IM were sufficient to achieve a clinical response.

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

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.

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.

Frequency of thiopurine methyltransferase mutation in patients of Mediterranean area with inflammatory bowel disease and autoimmune disorders.

BACKGROUND AND AIMS: Few studies exist on the frequency of thiopurine methyltransferase (TPMT) mutation in patients from Southern Europe. We aimed to evaluate the frequency of TPMT mutation in a homogeneous Sicilian cohort of patients with inflammatory bowel disease (IBD), autoimmune and hematological disorders, the rate of thiopurine-related adverse events, and its association with the TPMT genotype. RESULTS: Among 105 patients with IBD, 45 with autoimmune disease, and 34 with hematologic diseases, the homozygous TPMT variant genotype was found in one patient only (0.5%), while the heterozygous TPMT genotype was identified in 8 patients (4.3%). In patients with IBD, leukopenia was observed in ten patients: one had the homozygous TPMT genotype, one the heterozygous genotype, and the remaining eight the wild type genotype. CONCLUSIONS: The frequency of TPMT mutation in a Mediterranean area was low. TPMT genotyping is not a sensitive tool for predicting thiopurine-induced leukopenia.

Six year adalimumab efficacy in steroid-dependent Crohn's disease patients: A prospective single-center real life study.

BACKGROUND: Adalimumab is effective in the treatment of Crohn's disease. We have already reported data on the efficacy of adalimumab in 110 steroid-dependent patients. At the end of the study 90 patients (64.5%) maintained clinical remission. AIMS: To assess efficacy and safety of adalimumab after 6 years in patients of the original cohort who responded to treatment. METHODS: The present study is an extension of the published paper on 90/110 patients. We report results on clinical remission and safety of 6 year maintenance therapy with adalimumab. RESULTS: Of the original cohort 90 patients completed the study, 17 were lost to follow-up and 3 died. At the end of follow-up (74.16±10.3 months) 37/90 patients (41%) maintained clinical remission. Of these, 32 (86%) continued adalimumab and 5 (13%) discontinued treatment due to clinical remission and mucosal healing. Of the remaining 53/90 patients, 47 (52%) discontinued adalimumab due to clinical failure and 6 (7%) to adverse events. We obtained endoscopy data in 31/32 patients in clinical remission continuing adalimumab: 11 (36%) did not improve, 6 (19%) worsened, 14 (45%) improved. At univariable analysis no variables were related to treatment outcome. CONCLUSIONS: This "real life" prospective study shows that adalimumab is a long-term effective and safe maintenance treatment in steroid-dependent Crohn's disease patients.

Distribution of liver disease in a cohort of immigrants in Sicily: analysis of day-hospital admissions in a migration medicine unit.

The objective of this study was to evaluate the frequency of liver disease and its aetiology in a cohort of immigrants. We retrospectively examined the hospital discharge charts of all the immigrant patients presenting at our day hospital from July 2009 to June 2013, and after evaluating the anamnestic, clinical and laboratory data on these charts we identified subjects with liver disease and its various aetiologies. The total sample population consisted of 1218 patients, of whom 112 (9.2%) had a diagnosis of liver disease. More than two-thirds of the latter (67.8%) came from Africa, while 15.2% were from Asia and 17.0% from Eastern Europe. In most patients the disease was related to HBV (44.6%), followed by alcohol (25%) and then HCV or cryptogenic disease (both 15.2%). Forty-six patients had undergone liver biopsy, which showed eight cases of varying degrees of liver steatosis, 29 cases with a variable severity of chronic liver disease, eight cases with a definite picture of liver cirrhosis and one case of alcoholic hepatitis. These data show that a significant proportion of our immigrant population has liver disease and that the most frequent cause is hepatitis B infection.