Publications by authors named "Giovanni Galati"

33 Publications

Real-world experience with obeticholic acid in patients with primary biliary cholangitis.

JHEP Rep 2021 Apr 27;3(2):100248. Epub 2021 Jan 27.

Internal Medicine and Hepatology, University Campus Bio-Medico of Rome, Rome, Italy.

Background & Aims: Obeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions.

Methods: Patients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical response according to ; the secondary endpoint was the biochemical response according to , defined as normal levels of bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) at 12 months. Safety and tolerability were also assessed.

Results: We analysed 191 patients until at least 12 months of follow-up. Median age was 57 years, 94% female, 61 (32%) had cirrhosis, 28 (15%) had histologically proven overlap with autoimmune hepatitis (PBC-AIH). At 12 months, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed. Response rates were 42.9% according to , and 11% by . Patients with cirrhosis had lower response than patients without cirrhosis (29.5% 49.2%,  = 0.01), owing to a higher rate of OCA discontinuation (30% 12%,  = 0.004), although with similar ALP reduction (29.4% 34%,  = 0.53). Overlap PBC-AIH had a similar response to pure PBC (46.4% 42.3%,  = 0.68), with higher ALT reduction at 6 months (-38% -29%,  = 0.04). Thirty-three patients (17%) prematurely discontinued OCA because of adverse events, of whom 11 experienced serious adverse events. Treatment-induced pruritus was the leading cause of OCA discontinuation (67%).

Conclusions: Effectiveness and safety of OCA under real-world conditions mirror those in the Poise trial. Patients with cirrhosis had lower tolerability. Overlap PBC-AIH showed higher ALT reduction at 6 months compared with patients with pure PBC.

Lay Summary: Obeticholic acid (OCA) was shown to be effective in more than one-third of patients not responding to ursodeoxycholic acid in a real-world context in Italy. Patients with cirrhosis had more side effects with OCA, and this led to suspension of the drug in one-third of patients. OCA was also effective in patients who had overlap between autoimmune hepatitis and primary biliary cholangitis.
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http://dx.doi.org/10.1016/j.jhepr.2021.100248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930359PMC
April 2021

Current Treatment Options for HCC: From Pharmacokinetics to Efficacy and Adverse Events in Liver Cirrhosis.

Curr Drug Metab 2020 ;21(11):866-884

Unit of Clinical Medicine and Hepatology, University Campus Bio-Medico, Rome, Italy.

Background: Hepatocellular carcinoma (HCC) is among the world's most common cancers. For over ten years, the only medical treatment for it has been the multikinase inhibitor Sorafenib. Currently, however, other first or second-line therapeutic options have also shown efficacy against HCC, such as multikinase inhibitors (Regorafenib, Lenvatinib, and Cabozantinib), a monoclonal antibody against the vascular endothelial growth factor receptor 2 (Ramucirumab), and immune-checkpoint inhibitors (Nivolumab, Pembrolizumab, Ipilimumab).

Aim: The aim of this paper is to review the metabolic pathways of drugs that have been tested for the treatment of HCC and the potential influence of liver failure over those pathways.

Methods: The Food and Drug Administration (FDA)'s and European Medicines Agency (EMA)'s datasheets, results from clinical trials and observational studies have been reviewed.

Results: This review summarizes the current knowledge regarding targets, metabolic pathways, drug interactions, and adverse events of medical treatments for HCC in cirrhotic patients.

Conclusion: The new scenario of systemic HCC therapy includes more active drugs with different metabolic pathways and different liver adverse events. Clinical and pharmacological studies providing more data on the safety of these molecules are urgently needed.
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http://dx.doi.org/10.2174/1389200221999200918141239DOI Listing
January 2020

Diagnostic value of Virtual Touch Quantification (VTQ®) for differentiation of hemangiomas from malignant focal liver lesions.

Med Ultrason 2019 Nov;21(4):371-376

Hepatology and Clinical Medicine Unit of University Campus Bio Medico of Rome.

Aim: To evaluate the diagnostic value of Virtual Touch Quantification (VTQ®) for characterizing benign vs. malignant focal liver lesions (FLLs).

Material And Methods: From January 2015 to January 2016 all consecutive FLLs visualized during a conventional abdominal ultrasound (US), underwent VTQ® evaluation, taking five measurements of both the lesion and the surrounding parenchyma.

Results: We studied 119 FLLs, consisting of 52 hemangiomas (HEs), 39 hepatocellular carcinomas (HCCs), and 28 liver metastases (METs). HEs showed a significantly lower shear wave velocity (SWV) values compared to malignant FLLs (HEs SWV median value 1.34 m/sec, IQR 0.9; malignant lesions SWV median value 2.69 m/sec, IQR 1.6; p<0.001). Moreover, a nodule-to-parenchyma SWV ratio showed a significant difference in HEs and METs (p<0.001) but not in HCCs (p=0.03). SWV values were able to correctly differentiate malignant lesions with c-statistics of 0.82 (95 % CI 0.74- 0.90) and sensitivity of 74.6%/specificity of 80.7% at a cut-off of 2 m/sec.

Conclusions: Our results suggest that VTQ® is able to distinguish HEs from malignant lesions (HCCs and METs) at a SWV cut-off of 2 m/sec.
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http://dx.doi.org/10.11152/mu-2062DOI Listing
November 2019

Occurrence of hepatocellular carcinoma after direct-acting antiviral therapy for hepatitis C virus infection: literature review and risk analysis.

Expert Opin Drug Saf 2019 07 20;18(7):603-610. Epub 2019 May 20.

i Dipartimento di Scienze Mediche e Chirurgiche Alma Mater Studiorum , Università di Bologna , Bologna , Italy.

Introduction: Concerns were raised about a high occurrence of hepatocellular carcinoma (HCC) after successful treatment of chronic hepatitis C (CHC) by direct-acting antivirals (DAAs).

Areas Covered: The authors summarize the clinical studies reporting the occurrence rate and risk factors of HCC after DAAs in CHC.

Expert Opinion: The recent introduction of all-oral DAAs has substantially changed the scenario of CHC, achieving a sustained virological response (SVR) in >90% of cases. Earlier concerns raised about an increasing incidence of HCC post-DAAs were flawed by large heterogeneity of patients, the limited number of well-designed prospective studies (only nine, up to date) and the inclusion of a large number of patients with advanced liver disease, previously excluded from interferon-based studies. Current data on DAAs have shown a lower risk of HCC development; however, they were unable to identify patients at greater risk for HCC occurrence after SVR. Surveillance strategy, likely lifelong, is mandatory in these patients according to general expert opinion.
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http://dx.doi.org/10.1080/14740338.2019.1617272DOI Listing
July 2019

Lack of reduction in serum alpha-fetoprotein during treatment with direct antiviral agents predicts hepatocellular carcinoma development in a large cohort of patients with hepatitis C virus-related cirrhosis.

J Viral Hepat 2018 12 6;25(12):1493-1500. Epub 2018 Sep 6.

Liver and Transplant Unit, Tor Vergata University Hospital, Rome, Italy.

Risk of hepatocellular carcinoma (HCC) in hepatitis C virus cirrhotic patients treated with direct-acting antiviral agents (DAA) is still debating. We investigated it in a large cohort. The cohort comprised 1045 cirrhotic patients who completed treatment with DAA, with a median follow-up of 17.3 months after end of treatment (EOT), including 943 patients without history of HCC and 102 previously treated for HCC. The majority were men (59.9%), with compensated cirrhosis (88.8%), genotype 1b (44.7%). Univariate, multivariate analysis and Kaplan-Meier curves were performed to detect predictors of HCC in patients with and without reduction in alpha-fetoprotein (AFP) during treatment. SVR12 was 95.6%. HCC developed in 95 (9.9%), including 54 of 943 (5.7%) occurrent and 41 of 102 (39%) recurrent tumours. De novo were more often unifocal (P = 0.01) and curable (P = 0.03). AFP decreased from 16.1 ± 36.2 mg/dL (baseline) to 11.4 ± 55 mg/dL (EOT). At univariate analysis, predictors were a previous HCC, older age, higher model for end-stage liver disease, prolonged INR, lower platelets, baseline and EOT AFP, virological failure and no reduction in AFP during treatment. Kaplan-Meier curves showed lower incidence of HCC in patients showing any reduction in AFP (P = 0.001). Those with AFP <6 ng/mL had the lowest risk (P = 0.0002). At logistic regression, platelets (P = 0.009, OR 0.99 CI: 0.99-1.00), previous HCC (P < 0.000 01, OR: 10.76, 95% CI: 5.89-19.34) and no reduction in AFP during treatment (P = 0.0005, OR: 2.98, CI: 1.60-5.54) were independent predictors of HCC. In conclusion, risk of HCC after DAA treatment remains substantial. It is higher among patients with previous HCC, low platelets and without reduction in AFP during treatment.
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http://dx.doi.org/10.1111/jvh.12982DOI Listing
December 2018

Combining Genetic Variants to Improve Risk Prediction for NAFLD and Its Progression to Cirrhosis: A Proof of Concept Study.

Can J Gastroenterol Hepatol 2018 14;2018:7564835. Epub 2018 Mar 14.

Internal Medicine, Geriatrics, and Hepatology Unit, University Campus Bio-Medico, Rome, Italy.

Background & Aims: Identifying NAFLD patients at risk of progression is crucial to orient medical care and resources. We aimed to verify if the effects determined by different single nucleotide polymorphisms (SNPs) could add up to multiply the risk of NAFLD and NASH-cirrhosis.

Methods: Three study populations, that is, patients diagnosed with NASH-cirrhosis or with noncirrhotic NAFLD and healthy controls, were enrolled. PNPLA3 rs738409, TM6SF2 rs58542926, KLF6 rs3750861, SOD2 rs4880, and LPIN1 rs13412852 were genotyped.

Results: One hundred and seven NASH-cirrhotics, 93 noncirrhotic NAFLD, and 90 controls were enrolled. At least one difference in allele frequency between groups was significant, or nearly significant, for the PNPLA3, TM6SF2, and KLF6 variants ( < 0.001, < 0.05, and = 0.06, resp.), and a risk score based on these SNPs was generated. No differences were observed for SOD2 and LPIN1 SNPs. When compared to a score of 0, a score of 1-2 quadrupled, and a score of 3-4 increased 20-fold the risk of noncirrhotic NAFLD; a score of 3-4 quadrupled the risk of NASH-cirrhosis.

Conclusions: The effects determined by disease-associated variants at different can add up to multiply the risk of NAFLD and NASH-cirrhosis. Combining different disease-associated variants may represent the way for genetics to keep strength in NAFLD diagnostics.
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http://dx.doi.org/10.1155/2018/7564835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872672PMC
March 2019

Platelet count may impact on lysosomal acid lipase activity determination in dried blood spot.

Clin Biochem 2017 Aug 24;50(12):726-728. Epub 2017 Feb 24.

Internal Medicine and Hepatology Unit, University Campus Bio-Medico, Rome, Italy.

Background: We aimed to evaluate the influence of white blood cell (WBC) and platelet (PLT) counts on dried blood spot (DBS)-determined lysosomal acid lipase (LAL) activity in a large group of healthy subjects.

Methods: One-hundred-and-seventy-two healthy subjects aged ≥18 were enrolled. Complete clinical biochemistry and LAL activity in DBS were determined. In 35 subjects, WBCs and PLTs were isolated, and LAL activity was measured in both blood cell populations. Univariate and multivariate analyses to DBS-LAL activity were performed.

Results: Mean age of subjects was 44.8±17.2years, 43.6% were males, and mean DBS-LAL activity was normal (1.0±0.3nmol/spot/h). LAL activity in WBCs was significantly higher than in PLTs (458.9±133.6 vs 235.0±88.3nmol/mg/h, p<0.001). However, LAL activity in DBS correlated more strongly with that in PLTs (r=0.65, p<0.001) than with that in WBCs (r=0.49, p<0.01). Consistently, in the multivariate model, DBS-LAL activity was independently associated only with PLT count (β=0.39, p<0.001).

Conclusions: PLT number may impact on the result of the DBS-LAL test, and a consideration of PLT count is recommended before interpreting LAL activity in DBS.
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http://dx.doi.org/10.1016/j.clinbiochem.2017.02.013DOI Listing
August 2017

Hepatitis C and double-hit B cell lymphoma successfully treated by antiviral therapy.

World J Hepatol 2016 Oct;8(29):1244-1250

Giovanni Galati, Lorenzo Rampa, Umberto Vespasiani-Gentilucci, Alessandro Guidi, Antonio Picardi, Unit of Internal Medicine and Hepatology, Department of Medicine, Università Campus Bio-Medico di Roma, 00128 Rome, Italy.

B cells lymphoma is one of the most challenging extra-hepatic manifestations of hepatitis C virus (HCV). Recently, a new kind of B-cell lymphoma, named double-hit B (DHL), was characterized with an aggressive clinical course whereas a potential association with HCV was not investigated. The new antiviral direct agents (DAAs) against HCV are effective and curative in the majority of HCV infections. We report the first case, to our knowledge, of DHL and HCV-infection successfully treated by new DAAs. According to our experience, a DHL must be suspected in case of HCV-related lymphoma, and an early diagnosis could direct towards a different hematological management because a worse prognosis might be expected. A possible effect of DAAs on DHL regression should be investigated, but eradicating HCV would avoid life-threatening reactivation of viral hepatitis during pharmacological immunosuppression in onco-haematological diseases.
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http://dx.doi.org/10.4254/wjh.v8.i29.1244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067444PMC
October 2016

Breath-print analysis by e-nose may refine risk stratification for adverse outcomes in cirrhotic patients.

Liver Int 2017 02 21;37(2):242-250. Epub 2016 Aug 21.

Clinical Medicine and Hepatology Department, Campus Bio-Medico University, Rome, Italy.

Background & Aims: The spectrum of volatile organic compounds in the exhaled breath (breath-print, BP) has been shown to characterize patients with cirrhosis and with worse hepatic function. However, the association of different BPs with clinically relevant outcomes has not been described yet. Hence, we aimed to evaluate the association between BPs, mortality and hospitalization in cirrhotic patients and to compare it with that of the "classical" prognostic indices (Child-Pugh Classification [CPC] and MELD).

Methods: Eighty-nine cirrhotic patients (M/F 59/30, mean age 64.8 ± 11.3, CPC A/B/C 37/33/19) were recruited and followed up for a median time of 23 months. Clinical and biochemical data were collected. Breath collection and analysis were obtained through Pneumopipe and BIONOTE e-nose respectively.

Results: Four different BP clusters (A, B, C, D) were identified. BP clusters A and D were associated with a significantly increased risk of mortality (HR 2.9, 95% confidence intervals [CI] 1.5-5.6) and hospitalization (HR 2.6, 95% CI 1.4-4.6), even in multiple adjusted models including CPC and MELD score (adjusted [a]HR 2.8, 95% CI 1.1-7.0 for mortality and aHR 2.2, 95% CI 1.1-4.2 for hospitalization). CPC C maintained the strongest association with both mortality (aHR 17.6, 95% CI 1.8-174.0) and hospitalization (aHR 12.4, 95% CI 2.0-75.8).

Conclusions: This pilot study demonstrates that BP clusters are associated with significant clinical endpoints (mortality and hospitalization) even independently from "classical" prognostic indices. Even though further studies are warranted on this topic, our findings suggest that the e-nose may become an adjunctive aid to stratify the risk of adverse outcomes in cirrhotic patients.
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http://dx.doi.org/10.1111/liv.13214DOI Listing
February 2017

Hepatocellular Carcinoma in Alcoholic Liver Disease: Current Management and Recent Advances.

Rev Recent Clin Trials 2016 ;11(3):238-252

Internal Medicine and Hepatology Unit, Campus Bio Medico University of Rome, Italy.

Hepatocellular Carcinoma (HCC) is a major healthcare problem. Almost ninety percent of HCCs develops on cirrhosis due to chronic viral hepatitis, Non-Alcoholic Steatohepatitis (NASH) and alcohol abuse. Alcohol itself is defined a strong human carcinogenic agent. Some genetic polymorphisms in alcohol-metabolizing systems and more recently, some sequence variations within the genes coding for patatin-like phospholipase encoding 3 (PNPLA3) and Transmembrane 6 superfamily 2 (TM6SF2), have been found to promote liver fibrosis in alcohol abuse, until HCC development. The current management of HCC is related to tumor burden and liver function and it does not differ in alcoholics, although in alcoholics the surveillance for HCC could be less effective because socioeconomic context, such as the recall policy, the stage at the diagnosis and the prognosis are not different compared to viral HCCs. On regards of loco-regional treatment options, there have not been significant advances in the last few years, though an increasing role will be probably reserved to radio embolization and irreversible electroporation in the next future. Sorafenib (SOR) is still the only drug approved as systemic therapy in patients with HCC, whereas immunotherapy represents a promising approach for the treatment of HCC.
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http://dx.doi.org/10.2174/1574887111999160701091605DOI Listing
January 2018

Lysosomal Acid Lipase Activity Is Reduced Both in Cryptogenic Cirrhosis and in Cirrhosis of Known Etiology.

PLoS One 2016 24;11(5):e0156113. Epub 2016 May 24.

Internal Medicine and Hepatology Unit, University Campus Bio-Medico, Rome, Italy.

Conclusion: Liver cirrhosis is characterized by a severe acquired reduction of LAL-activity, the precise causes and consequences of which need to be further addressed. DBS-determined lysosomal enzyme activities seem to be affected by white blood cell and platelet counts, and the specificity of these tests can be reduced when applied to determined populations, such as cirrhotics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156113PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878774PMC
July 2017

The PNPLA3 rs738409 C > G polymorphism is associated with the risk of progression to cirrhosis in NAFLD patients.

Scand J Gastroenterol 2016 Aug 6;51(8):967-73. Epub 2016 May 6.

a Internal Medicine and Hepatology Unit , University Campus Bio-Medico , Rome , Italy ;

Background And Aims: The patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 C > G single nucleotide polymorphism (SNP) has been associated with steatosis and fibrosis in previous NAFLD populations in which cirrhotic patients were very poorly represented. Since not all NAFLD with fibrosis evolve to cirrhosis, we investigated the specific risk of cirrhosis conferred in NAFLD patients by carrying this SNP.

Methods: Three groups were studied: patients with NASH-cirrhosis; patients with biopsy-proven non-cirrhotic NAFLD; healthy subjects undergoing medicine check-ups. Epidemiological, anthropometric, and clinical data were collected, and the SNP was analyzed by pyrosequencing.

Results: Sixty-one patients with NASH-cirrhosis, 60 with non-cirrhotic NAFLD, and 125 healthy controls were included. Frequency of the PNPLA3 minor (G) allele was increased in patients with NASH-cirrhosis compared with non-cirrhotic NAFLD and controls (allele frequency: 0.598 versus 0.367 versus 0.2, respectively, p < 0.001), and different between the latter two groups (p < 0.001). Three-quarters (74%) of NASH cirrhotics carried at least one G allele, and almost half of them (46%) were GG homozygous. By multivariate analysis in the NAFLD population, each copy of the G allele was associated with an almost doubling of the risk of cirrhosis [OR 1.8 (1.02-3.2)], while being GG homozygous with a tripled risk compared with being CC homozygous [3.01 (1.03-10.8)].

Conclusions: In NAFLD patients, carriage of the PNPLA3G allele, and particularly of the GG genotype, is significantly associated with the risk of cirrhotic evolution. If confirmed in larger series, these results would suggest that most of NASH cases require the contribution of an altered PNPLA3 function to progress until cirrhosis.
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http://dx.doi.org/10.3109/00365521.2016.1161066DOI Listing
August 2016

Breath-print analysis by e-nose for classifying and monitoring chronic liver disease: a proof-of-concept study.

Sci Rep 2016 05 5;6:25337. Epub 2016 May 5.

Clinical Medicine and Hepatology Department, Campus Bio-Medico University, via Alvaro del Portillo 200, 00128 Rome, Italy.

Since the liver plays a key metabolic role, volatile organic compounds in the exhaled breath might change with type and severity of chronic liver disease (CLD). In this study we analysed breath-prints (BPs) of 65 patients with liver cirrhosis (LC), 39 with non-cirrhotic CLD (NC-CLD) and 56 healthy controls by the e-nose. Distinctive BPs characterized LC, NC-CLD and healthy controls, and, among LC patients, the different Child-Pugh classes (sensitivity 86.2% and specificity 98.2% for CLD vs healthy controls, and 87.5% and 69.2% for LC vs NC-CLD). Moreover, the area under the BP profile, derived from radar-plot representation of BPs, showed an area under the ROC curve of 0.84 (95% CI 0.76-0.91) for CLD, of 0.76 (95% CI 0.66-0.85) for LC, and of 0.70 (95% CI 0.55-0.81) for decompensated LC. By applying the cut-off values of 862 and 812, LC and decompensated LC could be predicted with high accuracy (PPV 96.6% and 88.5%, respectively). These results are proof-of-concept that the e-nose could be a valid non-invasive instrument for characterizing CLD and monitoring hepatic function over time. The observed classificatory properties might be further improved by refining stage-specific breath-prints and considering the impact of comorbidities in a larger series of patients.
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http://dx.doi.org/10.1038/srep25337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4857073PMC
May 2016

The calm before the storm: a report from the International Liver Cancer Association Congress 2015 - part 2.

Future Oncol 2016 Feb 18;12(3):285-8. Epub 2016 Jan 18.

Dipartimento di Gastroenterologia-UO Gastroenterologia e Malattie del Ricambio, Azienda Ospedaliero Universitaria Pisana, Ospedale Cisanello, 56126 Pisa PI, Italy.

International Liver Cancer Association Congress 2015, Paris, France, 4-6 September 2015 Since its creation 9 years ago, in 2007, the International Liver Cancer Association has focused on the multidisciplinary approach to liver cancer due to advances in hepatology science and care worldwide. In its 2015 annual conference, held on 4-6 September in Paris, France, the most recent progresses in the basic biology, management and treatment of liver cancer have been presented. This report, divided into two parts, introduces and critically reviews some of the most intriguing topics discussed at the meeting.
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http://dx.doi.org/10.2217/fon.15.324DOI Listing
February 2016

The calm before the storm: a report from the International Liver Cancer Association Congress 2015--part 1.

Future Oncol 2016 Feb 18;12(3):281-4. Epub 2016 Jan 18.

Dipartimento di Gastroenterologia-UO Gastroenterologia e Malattie del Ricambio, Azienda Ospedaliero Universitaria Pisana, Ospedale Cisanello, 56126 Pisa PI, Italy.

International Liver Cancer Association Congress 2015, Paris, France, 4-6 September 2015 Since its creation 9 years ago, in 2007, the International Liver Cancer Association has focused on the multidisciplinary approach to liver cancer due to advances in hepatology science and care worldwide. In its 2015 annual conference, held on 4-6 September in Paris, France, the most recent progresses in the basic biology, management and treatment of liver cancer have been presented. This report, divided into two parts, introduces and critically reviews some of the most intriguing topics discussed at the meeting.
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http://dx.doi.org/10.2217/fon.15.323DOI Listing
February 2016

Hepatitis C treatment in the elderly: New possibilities and controversies towards interferon-free regimens.

World J Gastroenterol 2015 Jun;21(24):7412-26

Umberto Vespasiani-Gentilucci, Giovanni Galati, Paolo Gallo, Antonio De Vincentis, Antonio Picardi, Internal Medicine and Hepatology Unit, University Campus Bio-Medico, 00128 Rome, Italy.

Due to the progressive aging of the hepatitis C virus (HCV) population which have acquired the infection during its maximum spread after the Second World War, the management of the elderly HCV-infected patient is emerging as a hot topic. Unfortunately, although it is recognized that the progression of HCV-related liver disease gets faster with aging, and that even extra-hepatic manifestations of HCV infection are probably worse in the elderly, till now, treatment attempts in this population have been significantly limited by the well-known contraindications and side effects of interferon (IFN). The arrival of several new anti-HCV drugs, and the possibility to combine them in safe and effective anti-viral regimens, is relighting the hope of a cure for many elderly patients who had been cut out of IFN-based treatments. However, although these new regimens will be certainly more manageable, it should be underscored that IFN-free doesn't mean free from any contraindication or side-effect. Moreover, one issue which promises to become central is that of the possible interactions between antiviral therapy and the multiple drugs frequently assumed by elderly patients because of comorbidities. In this review, we will revise the epidemiology pointing to HCV as an infection of the elderly, the evidences that HCV harms the health of the aged patient more than that of the young one, and the available experiences of HCV treatment in the elderly with the "old" IFN-based regimens and with the newer drugs. We will conclude that the availability of IFN-free regimens should prompt us to change our mind and consider a significantly larger number of possible candidates among elderly patients, who would take significant advantage from viral eradication. Rather than the anagraphic age, drug-drug interactions and, mainly in case of economic restrictions, an evaluation of life expectancy dependent on liver disease with respect to that dependent on comorbidities, are likely to be the key issues guiding treatment indication in the next future. The sooner we will change our mind with respect to an a priori obstacle for anti-HCV treatment in the elderly, the sooner we will begin to spare many aged HCV patients from avoidable liver-related complications.
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http://dx.doi.org/10.3748/wjg.v21.i24.7412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481436PMC
June 2015

European Association for the Study of the Liver Hepatocellular Carcinoma summit 2014: old questions, new (or few) answers?

Future Oncol 2014 Aug;10(10):1719-21

Dipartimento di Gastroenterologia-Unità Ospedaliera Gastroenterologia e Malattie del Ricambio, Azienda Ospedaliero Universitaria Pisana, Ospedale Cisanello, Pisa, Italy.

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http://dx.doi.org/10.2217/fon.14.102DOI Listing
August 2014

Determinants of alanine aminotransferase levels in a large population from Southern Italy: relationship between alanine aminotransferase and age.

Dig Liver Dis 2014 Oct 19;46(10):909-15. Epub 2014 Jun 19.

Internal Medicine and Hepatology Unit, University Campus Bio-Medico of Rome, Italy.

Background: Determinants of alanine aminotransferase levels have never been investigated in real-life settings. The relationship between alanine aminotransferase and age remains controversial. We evaluated epidemiological, anthropometric, and metabolic factors associated with alanine aminotransferase, focusing on the relationship between alanine aminotransferase and age.

Methods: A 5-year retrospective analysis was performed on data recorded by 120 general practitioners from Naples (Italy), caring for 170,000 subjects. Exclusion criteria were age <18 years, diagnosis of chronic liver disease, positive markers for viral hepatitis, alcohol abuse, and alanine aminotransferase >100UI/L.

Results: 44,232 subjects were enrolled (42.7% males, mean age 56±18 years). Alanine aminotransferase showed independent direct associations with body mass index, glycaemia, cholesterol, and triglycerides (p<0.001), and inverse associations with high-density lipoprotein cholesterol (p<0.001) and creatinine (p<0.01). The relationship between alanine aminotransferase and age was better expressed by polynomial regression (r=0.18, p<0.001), creating an inverted parabola. Mean alanine aminotransferase increased until the third decade in males and the fifth in females, with a subsequent progressive decrease in both genders. The inverse association between alanine aminotransferase and age in older subjects was independent from metabolic factors.

Conclusions: This real-life setting study, supports the concept that dysmetabolism is a strong determinant of liver injury. Based on our data, a reduction of the standard upper limit of normal alanine aminotransferase should be considered for older subjects.
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http://dx.doi.org/10.1016/j.dld.2014.05.021DOI Listing
October 2014

EASL HCC summit: liver cancer management.

Future Oncol 2014 May;10(7):1129-32

Dipartimento di Gastroenterologia-UO Gastroenterologia e Malattie del Ricambio, Azienda Ospedaliero Universitaria Pisana, Ospedale Cisanello Via Paradisa 2, 56124 Pisa, Italy.

EASL HCC Summit, Geneva, Switzerland, 13-16 February 2014. The European Association for the Study of the Liver (EASL) organized the 2014 EASL HCC Summit in Geneva, Switzerland. We discuss here the most interesting and provocative contents from the clinical program of the summit. The objective of this segment was to provide an in-depth review on the different management issues related to early detection, diagnosis and treatment of hepatocellular carcinoma, and, in addition, to highlight the ways of dealing with such an important and rapidly involving field.
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http://dx.doi.org/10.2217/fon.14.68DOI Listing
May 2014

Coexistence of HBsAg and HBsAb in a difficult-to-treat chronic hepatitis B: loss of HBsAg with entecavir plus tenofovir combination.

BMC Gastroenterol 2014 May 17;14:94. Epub 2014 May 17.

Clinical Medicine and Hepatology Unit, Campus Bio Medico University of Rome, 200, Alvaro Del Portillo Street, Rome 00128, Italy.

Background: Some reports have documented the coexistence of Hepatitis B surfage Antigen (HBsAg) and anti-HBsAg antibodies (HBsAb) in patients with chronic hepatitis B (CHB), often in the absence of amino acid substitutions in the HBsAg sequences of the Hepatitis B Virus (HBV) genome able to explain an immunological escape variant.HBV genome has a very compact coding organization, with four partially overlapping open reading frames (ORFs). Because the reverse transcriptase region (rt) of HBV polymerase overlaps the HBsAg ORF, it is possible that some mutations in the HBsAg region correspond to mutations in the rt ORF, conferring resistance to current antiviral therapies. This unique case explores the response to antiviral therapies of a CHB with concurrent HBsAg and HBsAb positivity, and analyse the clinical implications of possible mutations in rt and HBsAg ORFs.

Case Presentation: Here we describe the case of a 59 year-old Italian man suffering from Hepatitis B envelope Antigen (HBeAg) positive CHB with concurrent HBsAb positivity. By ultra-deep pyro-sequencing (UDPS) technique, mutations conferring immunological escape or resistance to antiviral therapies were found neither in HBsAg nor in HBV rt ORFs, respectively. The patient was unsuccessfully treated with interferon, adefovir monotherapy and adefovir plus entecavir combination. Surprisingly, during entecavir plus tenofovir combination, anti-HBe seroconversion and HBsAg loss were observed, while the titer of HBsAb persisted.

Conclusions: Concurrent HBsAg/HBsAb positivity in active CHB is a clinical and virological dilemma. In this setting, there are not consistent data about the response to conventional therapies and the immunological balance between host and virus remains so far unexplained. This is, to our knowledge, the first case described of a CHB with HBsAg/HBsAb positivity, wild type for clinically relevant mutations in HBsAg and rt ORFs, successfully treated with a combination of nucleot(s)ide analogues (NAs).
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http://dx.doi.org/10.1186/1471-230X-14-94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031327PMC
May 2014

Transarterial chemoembolization and sorafenib in hepatocellular carcinoma.

Expert Rev Anticancer Ther 2014 Jul 22;14(7):831-45. Epub 2014 May 22.

Section of Gastroenterology, DIBIMIS, University of Palermo, 90127 Palermo, Italy.

Transarterial chemoembolization (TACE) is considered as the standard therapy for patients with intermediate-stage hepatocellular carcinoma. However, given the high heterogeneity of this population, no common strategy or protocol standardization has been defined yet. In the last few years TACE treatment has been combined with sorafenib systemic therapy, reporting overall positive results both in terms of safety and efficacy. This systematic review presents and critically discusses the evidence available on the use of TACE in combination (concomitant or sequential) with sorafenib, focusing also on clinical trials currently ongoing to better define an optimal therapeutic strategy for this group of patients.
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http://dx.doi.org/10.1586/14737140.2014.920694DOI Listing
July 2014

Hepatitis C virus and metabolic disorder interactions towards liver damage and atherosclerosis.

World J Gastroenterol 2014 Mar;20(11):2825-38

Umberto Vespasiani-Gentilucci, Paolo Gallo, Antonio De Vincentis, Giovanni Galati, Antonio Picardi, Internal Medicine and Hepatology Unit, University Campus Bio-Medico of Rome, 00128 Rome, Italy.

Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide, and alterations of glucose metabolism have reached pandemic proportions in western countries. However, the frequent coexistence between these two conditions is more than simply coincidental, since HCV can induce insulin resistance through several mechanisms. Indeed, the virus interferes with insulin signaling both directly and indirectly, inducing the production of pro-inflammatory cytokines. Furthermore, the entire viral life cycle has strict interconnections with lipid metabolism, and HCV is responsible for a "viral" steatosis which is frequently superimposed to a "metabolic" one. Several evidences suggest that HCV-induced metabolic disorders contribute both to the evolution of liver fibrosis and, likely, to the progression of the other disorders which are typically associated with altered metabolism, in particular atherosclerosis. In the present review, we will examine in depth the links between HCV infection and insulin resistance, liver steatosis and diabetes, and analyze the impact of these interactions on the progression of liver fibrosis and atherosclerosis. Special attention will be focused on the highly debated topic of the relationship between HCV infection and cardiovascular disease. The available clinical literature on this item will be broadly reviewed and all the mechanisms possibly implied will be discussed.
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http://dx.doi.org/10.3748/wjg.v20.i11.2825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961987PMC
March 2014

Hepatic toll-like receptor 4 expression is associated with portal inflammation and fibrosis in patients with NAFLD.

Liver Int 2015 Feb 5;35(2):569-81. Epub 2014 Apr 5.

Clinical Medicine and Hepatology Unit, University Campus Bio-Medico of Rome, Rome, Italy.

Background & Aims: Notwithstanding evidences implicating the lipopolysaccharides (LPS)/toll-like receptor-4 (TLR4) axis in the pathogenesis of NAFLD, there are no studies aimed to characterize hepatic TLR4 expression in NAFLD patients. We aimed to analyse hepatic TLR4 expression and to verify its relationship with disease activity/evolution in NAFLD patients.

Methods: Liver tissue from 74 patients with NAFLD and 12 controls was analysed by immunohistochemistry (IHC) for TLR4, α-smooth muscle actin (α-SMA) and cytokeratin-7. IHC for α-SMA was used to evaluate activation of fibrogenic cells (hepatic stellate cells and portal/septal myofibroblasts), that for cytokeratin-7 to count hepatic progenitor cells and bile ducts/ductules, and that for CD68, in a subgroup of 27 patients, for detecting macrophages. Serum LPS-binding protein (LBP), a sensitive marker of LPS activity, was determined in 36 patients and 32 controls.

Results: As confirmed by double-labelling experiments, the highest level of TLR4 expression was observed in hepatic progenitor cells, biliary cells and portal/septal macrophages. TLR4-positive hepatic progenitor cells and bile ducts/ductules correlated with portal/interface inflammation, activity of fibrogenic cells and fibrosis (P < 0.001). Also the score of TLR4 positivity of porto-septal inflammatory infiltrate correlated with number of hepatic progenitor cells and bile ducts/ductules, activity of fibrogenic cells and fibrosis (P < 0.01). Serum LBP was increased in patients compared to controls (P < 0.001), and correlated with portal/interface inflammation, activity of portal/septal myofibroblasts and fibrosis (all P < 0.05).

Conclusions: TLR4 expression by regenerating and inflammatory cells at the porto-septal and interface level, favoured by increased LPS activity, is associated with activation of fibrogenic cells and the degree of fibrosis.
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http://dx.doi.org/10.1111/liv.12531DOI Listing
February 2015

Cardiotrophin-1 is not associated with carotid or coronary disease and is inversely associated with obesity in patients undergoing coronary angiography.

Arch Med Sci 2013 Aug 29;9(4):635-9. Epub 2013 Aug 29.

Campus Bio-Medico of University, Clinical Medicine - Hepatology, Rome, Italy.

Introduction: Cardiotrophin-1 (CT-1) is a member of the interleukin-6 superfamily with known hypertrophic and protective actions upon cardiac myocytes. Although its effects on myocardial tissue and its role in hypertensive heart disease are well documented, there are no studies on CT-1 blood levels in patients with coronary artery disease. In this study we aimed to verify the relationships of serum CT-1 with vascular disease and metabolic parameters in a population of patients undergoing coronary angiography due to clinical indications.

Material And Methods: Serum levels of CT-1 were investigated in a cohort of 81 consecutive patients (median age 68 years (95% CI: 64-71), 59 males) undergoing coronary angiography and carotid Doppler ultrasound. Exclusion criteria were: acute coronary syndrome, already-established ischemic cardiopathy, chronic inflammatory diseases and presence or past history of cancer.

Results: Levels of CT-1 were inversely correlated with body mass index (BMI) and waist circumference (WC) (ρ = -0.261, p = 0.02; ρ = -0.224, p = 0.05, respectively). Moreover, obese patients showed significantly lower CT-1 concentrations than non-obese ones (1.18 (0.64-1.64) ng/ml vs. 1.56 (1.37-2.04) ng/ml, p = 0.013), and serum CT-1 was significantly reduced in patients with elevated compared to those with normal WC (1.43 (0.94-1.60) ng/ml vs. 1.64 (1.39-2.49) ng/ml, p = 0.047). Concentrations of CT-1 did not correlate either with the other parameters of metabolic syndrome or with markers of cardiovascular disease (carotid intima-media thickness, presence of carotid or coronary artery plaques).

Conclusions: Our results failed to demonstrate any association between CT-1 and carotid or coronary disease. The inverse association with BMI and WC fits with the latest experimental data on the role of CT-1 in dysmetabolic conditions and could help to further clarify the role of CT-1 in obesity and diabetes.
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http://dx.doi.org/10.5114/aoms.2013.37272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776189PMC
August 2013

A case of Henoch-Schönlein purpura in the elderly: not just a 'second childhood'.

Aging Clin Exp Res 2012 Oct 25;24(5):559-60. Epub 2012 Jun 25.

Department of Clinical Medicine and Rheumatology, Campus Bio-Medico University, Rome, Italy.

Henoch-Schönlein Purpura (HSP) is a small vessel-vasculitis that usually affects children and adolescents; its onset in adults is uncommon.We describe a case of HSP complicated with nephritis and extensive deep vein thrombosis in an 81-year-old Caucasian woman, successfully treated with oral corticosteroids. Even at the extremes of age, HSP should be considered in the differential diagnosis of leukocytoclastic vasculitis, with a particular attention to renal involvement, because of its potential morbidity and mortality in the elderly; in addition, ruling out an occult thrombotic event in course of HSP is mandatory, especially in the presence of additional thrombotic risk factors.
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http://dx.doi.org/10.3275/8476DOI Listing
October 2012

Deep vein thrombosis, inferior vena cava interruption and multiple thrombophilic gene mutations.

Am J Med Sci 2011 Jul;342(1):79-82

Clinical Medicine and Hepatology Unit, University Campus Bio-Medico of Rome, Italy.

Interruption or hypoplasia of the inferior vena cava, with associated azygos continuation, is an uncommon congenital vascular malformation (Ellis et al, Comput Radiol 1986;10:15-22). Although this anomaly causes venous stasis, few patients present with history of deep vein thrombosis (DVT). The exact role of coexisting thrombophilic gene mutations, also heterozygotic, is far from being completely understood. However, in these cases, because of a probable additive effect, treatment of complications and careful prophylaxis for recurrent DVT are recommended lifelong. The authors report a case of inferior vena cava interruption with azygos continuation in a 30-year-old woman who presented with a history of recurrent lower limb DVT. In addition, heterozygosis for the H1299R polymorphism of the factor V gene (Factor V HR2), for the C677T polymorphism of the methylenetetrahydrofolate reductase gene (MTHFR C677T) and for the 4G/5G polymorphism of the plasminogen activator inhibitor-1 gene (PAI-1 4G/5G) was found in DNA analyses.
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http://dx.doi.org/10.1097/MAJ.0b013e3182172758DOI Listing
July 2011

Non-cirrhotic portal hypertension with large regenerative nodules: a diagnostic challenge.

World J Gastroenterol 2011 May;17(20):2580-4

Clinical Medicine and Hepatology Unit, University Campus Bio-Medico of Rome, 00128 Rome, Italy.

Non-cirrhotic portal hypertension is a poorly understood condition characterized by portal hypertension in the absence of conventional hepatic cirrhosis and described in association with blood coagulation disorders, myeloproliferative and immunological diseases and with exposure to toxic drugs. Very recently, precise classification criteria have been proposed in order to define four distinct subcategories. The present case highlights how the clinical presentation, the confounding results from imaging studies, and the difficulties in the histological evaluation often render cases of non-cirrhotic portal hypertension a real diagnostic challenge. It also underscores the classification problems which can be faced once this diagnosis is performed. Indeed, the different subcategories proposed result from the prevalent subtypes in a spectrum of hepatic regenerative responses to a variety of injuries determining microcirculatory disturbances. More flexibility in classification should derive from this etiopathogenic background.
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http://dx.doi.org/10.3748/wjg.v17.i20.2580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103817PMC
May 2011

Angiogenic cytokines in patients undergoing antiviral treatment for chronic hepatitis C virus infection.

J Interferon Cytokine Res 2011 Feb 27;31(2):207-10. Epub 2010 Sep 27.

Internal Medicine and Hepatology Unit, University Campus Bio-Medico of Rome, Rome, Italy.

During chronic liver disease (CLD), angiogenesis participates in the fibrogenic process. Herein, we aimed at verifying the on-treatment kinetics of serum vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) in hepatitis C virus (HCV) patients undergoing antiviral therapy. Forty-three HCV patients treated with pegylated-interferon/ribavirin and 26 controls were studied. Serum VEGF and Ang-2 were determined before treatment, at different time points during treatment, and at follow-up after treatment. Thirty and 13 patients were sustained virological responder (SVR) and No-SVR, respectively. Patients showed increased Ang-2 levels [504 (368-720) versus 449 (389-483) pg/mL, P < 0.05], and equivalent VEGF levels [271 (193-377) versus 274 (199-324) pg/mL, P = 0.6], with respect to controls. By univariate analysis, stage of fibrosis was associated with Ang-2 levels (odds ratio 4.25, P < 0.05). In SVR patients VEGF levels showed a progressive reduction (P < 0.05) but returned to pretherapy levels at follow-up, and Ang-2 levels showed an opposite progressive increase, being significantly reduced at follow-up (P < 0.01). No significant modifications in VEGF and Ang-2 levels were observed in No-SVR. We conclude that, in patients with HCV-CLD, Ang-2 serum levels are associated with fibrosis and reduced at follow-up in SVR patients. On-treatment, VEGF and Ang-2 serum levels undergo different-sided modifications only in SVR patients, possibly expressing the vascular remodeling occurring early after viral clearance.
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http://dx.doi.org/10.1089/jir.2010.0040DOI Listing
February 2011

A mocking finding: portal cavernoma mimicking neoplastic mass. First sign of myeloproliferative disorder in a patient with Janus kinase2 V617F mutation.

Eur J Gastroenterol Hepatol 2009 Feb;21(2):233-6

Department of Clinical Medicine and Hepatology, GI Endoscopy Unit, University Campus Bio-Medico of Rome, Rome, Italy.

The most important systemic etiological factors for portal thrombosis are the thrombophilic conditions associated with myeloproliferative disorders (MPDs), either clinically manifest or so-called 'occult'. Latest studies have revealed a strong association between MPDs and a somatic point mutation (V617F) of the tyrosine kinase Janus kinase2. The 'pseudo-cholangiocarcinoma sign' is a well described radiological finding related to portal cavernoma. We describe the case of a 48-year-old man, presenting with cavernomatous transformation of an extrahepatic thrombotic obstruction of the portal vein mimicking a neoplastic mass of the hepatic hilum, who did not present any other cause for thrombosis except for the V617F Janus kinase2 mutation, suggesting an underlying MPD.
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http://dx.doi.org/10.1097/MEG.0b013e3283207b5aDOI Listing
February 2009