Sustained virological response in patients with HCV treated with daclatasvir plus sofosbuvir, with or without ribavirin: a large, field-practice study.

BACKGROUND: The once-daily oral combination of daclatasvir (DCV) and sofosbuvir (SOF), with or without ribavirin (RBV), is effective and well tolerated in patients with hepatitis C virus (HCV). However, further field-practice studies are necessary to investigate the effectiveness and safety of the DCV+SOF combination in diverse subpopulations of patients with HCV, including those who are more challenging to treat such as patients with a genotype 3 (G3) infection. The aim of this retrospective, multicenter, field-practice study was to investigate the therapeutic efficacy and safety of the oral combination of DCV and SOF, with or without RBV (DCV+SOF±RBV), in a large unselected cohort of patients with chronic HCV infection (CHC). PATIENTS AND METHODS: Consecutive patients received DCV+SOF±RBV for 12 or 24 weeks. The efficacy endpoint was sustained virological response at 12 weeks after the end of treatment (SVR12). Safety factors were also considered. RESULTS: A total of 620 patients were included in this study; the predominant genotype was G3 (55.3%). Of the total sample, 248 (40%) patients were treated with DCV+SOF+RBV and 372 (60%) did not receive RBV. The majority of patients assessed at week 12 (98%, 596/608) achieved SVR12. Among G3 patients, 98.8% (335/339) achieved SVR12. The most common adverse event was elevated bilirubin (30.6%), recorded in 4.9% of cases as a grade 3-4 adverse event. CONCLUSION: This study shows the high pan-genotypic effectiveness and safety of the DCV+SOF±RBV combination in a large, unselected sample of CHC patients with G1-4, including a wide proportion of G3 CHC patients.

Epidemiological, demographic and clinical data on chronic viral hepatitis C in Tuscany.

BACKGROUND: Recent introduction of direct antiviral agents (DAAs) has completely changed the scenario regarding hepatitis C virus (HCV) treatment. Certain countries' economic health programs prioritize DAAs according to specific clinical features of HCV-infected patients. The aim of this study was to define epidemiological, demographic and clinical characteristics of HCV-infected patients in the Tuscany region of central Italy. METHODS: We enrolled HCV patients with chronic viral hepatitis who were referred to the outpatient services of 16 hospitals in Tuscany from 1 January 2015 to 31 December 2015. Case report forms contained patient information including main demographic data, blood chemistry data, viral hepatitis markers, instrumental evaluations (liver biopsy or transient elastometry, liver ultrasound), eligibility for DAAs, and liver transplantation or therapy already in progress. RESULTS: Of all patients considered, 2919 HCV patients were enrolled (mean age: 57.44 ± 15.15; 54% males, 46% females). All routes of transmission were well represented (intravenous drug use in 20.7%; nosocomial/dental care in 20.6%; and coagulation factors/blood transfusions in 13.3%). Diabetes was the highest represented comorbidity (20.8%), followed by metabolic syndrome (15.5%) and ischemic heart disease (6.2%). The most prevalent HCV genotypes were 1b (47.4%) and 2 (16.5%). In the whole cohort of patients, 32.8% were cirrhotic (40 patients were listed for liver transplantation). Signs of portal hypertension were present mostly in the group older than 45 years (92.3%). Extrahepatic HCV-related diseases were present in 13.3% of cases (cryoglobulinemic syndrome in 58.3% and B-cell non-Hodgkin's lymphoma in 10.5%). CONCLUSIONS: Our study provides evidence of a high prevalence of epidemiological changes in HCV infection with a major prevalence of advanced liver disease, such as portal hypertension, in this elderly cohort of patients.

Clinical outcomes with long-term sorafenib treatment of patients with hepatocellular carcinoma: a multicenter real-life study.

AIM: This multicenter field-practice study evaluates outcomes of long-term sorafenib in hepatocellular carcinoma (HCC) patients. METHODS: Consecutive HCC patients on sorafenib were enrolled. We evaluated those receiving sorafenib for ≥12 months. RESULTS: Out of 800 patients on sorafenib, 81 (10%) received long-term treatment. Median duration of treatment was 22.7 months (range: 12.3-92.6). Only 21 (26%) reported grade 3/4 adverse events. Complete response was reported in 11 patients (14%). Median overall survival was 34.8 months (95% CI: 29.9-44.3). Only baseline Child-Pugh class was associated with survival. CONCLUSION: Sorafenib could result in long-term control of HCC in a relevant proportion of patients. Given the availability of regorafenib in the second-line setting, an earlier introduction of systemic therapy may be considered according to clinical indications.

Clinical epidemiology of chronic viral hepatitis B: A Tuscany real-word large-scale cohort study.

AIM: To build a regional database of chronic patients to define the clinical epidemiology of hepatitis B virus (HBV)-infected patients in the Tuscan public health care system. METHODS: This study used a cross-sectional cohort design. We evaluated chronic viral hepatitis patients with HBV referred to the outpatient services of 16 hospital units. Information in the case report forms included main demographic data, blood chemistry data, viral hepatitis markers, instrumental evaluations, and eligibility for treatment or ongoing therapy and liver transplantation. RESULTS: Of 4015 chronic viral hepatitis patients, 1096 (27.3%) were HBV infected. The case report form was correctly completed for only 833 patients (64% males, 36% females; mean age 50.1 ± 15.4). Of these HBV-infected patients, 73% were Caucasian, 21% Asian, 4% Central African, 1% North African and 1% American. Stratifying patients by age and nationality, we found that 21.7% of HBV-infected patients were aged < 34 years (only 2.8% were Italian). The most represented routes of transmission were nosocomial/dental procedures (23%), mother-to-child (17%) and sexual transmission (12%). The most represented HBV genotypes were D (72%) and A (14%). Of the patients, 24.7% of patients were HBeAg positive, and 75.3% were HBeAg negative. Of the HBV patients 7% were anti-HDV positive. In the whole cohort, 26.9% were cirrhotic (35.8% aged < 45 years), and 47% were eligible for or currently undergoing treatment, of whom 41.9 % were cirrhotic. CONCLUSION: Only 27.3% of chronic viral hepatitis patients were HBV infected. Our results provide evidence of HBV infection in people aged < 34 years, especially in the foreign population not protected by vaccination. In our cohort of patients, liver cirrhosis was also found in young adults.

Bismuth-based quadruple therapy following H. pylori eradication failures: a multicenter study in clinical practice.

BACKGROUND AND AIMS: Helicobacter pylori (H. pylori) eradication in patients who failed one or more therapeutic attempts remains challenging. This study aimed to assess the efficacy of three-in-one capsules bismuth-based quadruple therapy (Pylera®) in these patients managed in clinical practice. METHODS: This was a prospective, open-label, multicenter study enrolling consecutive, adult patients with persistent H. pylori infection following at least one standard therapy. All patients received a rescue quadruple therapy with Pylera (3 capsules four times daily) and esomeprazole 20 mg (1 tablet twice daily) for 10 days. H. pylori eradication was assessed by using Urea Breath Test 4-6 weeks following therapy ending. H. pylori eradication rates, compliance, and side-effects were calculated. RESULTS: A total of 208 patients in the 9 participating centres were enrolled. Overall, 180 patients were successfully cured from the infection, accounting for 86.5% (95% CI 81.9-91.2) and 92.3% (95% CI 88.6-96.1) eradication rates at intention-to-treat analysis and at per protocol analysis, respectively. Cure rates were similar across patients who failed one to three previous therapy attempts, but the success rate fell to 67% after 4 or more therapy failures. Compliance to therapy was good in 198 (95.2%) patients, whilst in 7 (5.3%) cases the therapy was interrupted within 5 days due to side effects. A total of 97 (46.6%) patients complained of at least one side effect; nausea, diarrhea and vomiting were the most frequently reported. CONCLUSIONS: Our study found that this bismuth-based quadruple therapy is highly effective as second-line and rescue therapy for H. pylori eradication in clinical practice.

Transarterial chemoembolization for the treatment of hepatocellular carcinoma: a review.

According to the current European Association for the Study of Liver guidelines, transarterial chemoembolization (TACE) is the recommended first-line therapy for patients with intermediate-stage (Barcelona Clinic Liver Cancer-B class) hepatocellular carcinoma (HCC). The efficacy of this therapy is supported by robust evidence; however, there is still a lack of standardization in treatment methodology, and TACE protocols are widely variable. Moreover, TACE can be associated with a number of contraindications. Despite these limitations, research on TACE is still ongoing with the aim of optimizing the use of this methodology in the current management of HCC. In particular, TACE represents a control in comparative studies, and it is currently being investigated in combination schemes, for example, with sorafenib. In this review, we briefly describe the current scenario and the clinical innovations regarding TACE for the treatment of HCC.

Report from European Association for the Study of the Liver: HCC Summit, Geneva, Switzerland, 2-5 February 2017.

The European Association for the Study of the Liver Hepatocellular Carcinoma (HCC) international meeting held in Geneva in February 2017 focused on the state of the art of HCC management, from diagnosis to treatment and the potential development of clinical research in this field. This report reviews some of the most interesting topics discussed at the meeting such as the role of hepatitis C viral infection treatment with direct-acting antivirals in enhancing HCC risk, current prognostic systems, early diagnosis techniques, curative therapies for early HCC and the systemic treatments for advanced disease with a look into future perspectives.

Transarterial radioembolization for hepatocellular carcinoma: a review.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is the second cause of death due to malignancy in the world. The treatment of HCC is complex and includes potentially curative and palliative approaches. However, both curative and palliative treatments for HCC are often associated with a not-completely favorable safety/efficacy ratio. Therefore, other treatment options appear necessary in clinical practice. Transarterial radioembolization has shown a promising efficacy in terms of disease control and is associated with a good safety profile. This review discusses the use of transarterial radioembolization in HCC, with a focus on the clinical aspects of this therapeutic strategy.

Curative therapies for hepatocellular carcinoma: an update and perspectives.

Curative treatments, including liver transplantation, surgical resection and percutaneous treatments, are the recommended therapies in BCLC-0 (Barcelona Clinic of Liver Cancer) or BCLC-A hepatocellular carcinoma (HCC). This review provides an overview of some issues of clinical importance concerning curative treatments in HCC.

Transarterial radioembolization for hepatocellular carcinoma: An update and perspectives.

In the last decade trans-arterial radioembolization has given promising results in the treatment of patients with intermediate or advanced stage hepatocellular carcinoma (HCC), both in terms of disease control and tolerability profile. This technique consists of the selective intra-arterial administration of microspheres loaded with a radioactive compound (usually Yttrium(90)), and exerts its therapeutic effect through the radiation carried by these microspheres. A careful and meticulous selection of patients is crucial before performing the radioembolization to correctly perform the procedure and reduce the incidence of complications. Radioembolization is a technically complex and expensive technique, which has only recently entered clinical practice and is supported by scant results from phase III clinical trials. Nevertheless, it may represent a valid alternative to transarterial chemoembolization (TACE) in the treatment of intermediate-stage HCC patients, as shown by a comparative retrospective assessment that reported a longer time to progression, but not of overall survival, and a more favorable safety profile for radioembolization. In addition, this treatment has reported a higher percentage of tumor shrinkage, if compared to TACE, for pre-transplant downsizing and it represents a promising therapeutic option in patients with large extent of disease and insufficient residual liver volume who are not immediately eligible for surgery. Radioembolization might also be a suitable companion to sorafenib in advanced HCC or it can be used as a potential alternative to this treatment in patients who are not responding or do not tolerate sorafenib.

Assessment of clinical and radiological response to sorafenib in hepatocellular carcinoma patients.

Sorafenib is an effective anti-angiogenic treatment for hepatocellular carcinoma (HCC). The assessment of tumor progression in patients treated with sorafenib is crucial to help identify potentially-resistant patients, avoiding unnecessary toxicities. Traditional methods to assess tumor progression are based on variations in tumor size and provide unreliable results in patients treated with sorafenib. New methods to assess tumor progression such as the modified Response Evaluation Criteria in Solid Tumors or European Association for the Study of Liver criteria are based on imaging to measure the vascularization and tumor volume (viable or necrotic). These however fail especially when the tumor response results in irregular development of necrotic tissue. Newer assessment techniques focus on the evaluation of tumor volume, density or perfusion. Perfusion computed tomography and Dynamic Contrast-Enhanced-UltraSound can measure the vascularization of HCC lesions and help predict tumor response to anti-angiogenic therapies. Mean Transit Time is a possible predictive biomarker to measure tumor response. Volumetric techniques are reliable, reproducible and time-efficient and can help measure minimal changes in viable tumor or necrotic tissue, allowing the prompt identification of non-responders. Volume ratio may be a reproducible biomarker for tumor response. Larger trials are needed to confirm the use of these techniques in the prediction of response to sorafenib.

Correlation between LDH levels and response to sorafenib in HCC patients: an analysis of the ITA.LI.CA database.

BACKGROUND: Lactate dehydrogenase (LDH) is a predictor of clinical outcome in hepatocellular carcinoma (HCC) patients. However, its predictive role in the clinical outcomes of sorafenib treatment has been poorly documented. The correlation between LDH levels and clinical outcomes in HCC patients treated with sorafenib and included in the nationwide Italian database ITA.LI.CA was investigated here. PATIENTS AND METHODS: The ITA.LI.CA database contains data for 5,136 HCC patients. All patients treated with sorafenib treatment and with available LDH values were considered. Overall survival (OS) and time to progression (TTP) were compared in patients with LDH levels above and below a defined threshold, determined through an ROC analysis. An explorative analysis investigated the relationship between the variation of LDH levels during treatment and response to sorafenib. RESULTS: Baseline LDH levels were available for 97 patients. The most accurate cutoff value for LDH concentration was 297 U/L. Patients with LDH values above (n=45) and below (n=52) this threshold showed equal OS (12.0 months) and TTP (4.0 months) values. Data on LDH levels during sorafenib treatment were reported for 10 patients. LDH values decreased in 3 patients (mean difference = -219 U/L) who also reported a prolonged OS and TTP versus those with unmodified/increased LDH (OS: NE (not evaluated) vs. 8.0 months, p=0.0083; TTP: 19.0 vs. 3.0 months, p=0.008). CONCLUSIONS: The clinical benefits of sorafenib do not seem to be influenced by baseline LDH. According to the results of an explorative analysis, however, a decreased LDH concentration during sorafenib might be associated with improved clinical outcomes.

Adacolumn leucocytapheresis for ulcerative colitis: clinical and endoscopic features of responders and unresponders.

Cytokines such as TNF-α have a validated role in the immunopathogensis of ulcerative colitis (UC), and intercepting inflammatory cytokines is currently the best option for maximizing treatment efficacy. One of the major sources of inflammatory cytokines are myeloid linage leucocytes (granulocytes, monocytes), which are present in great numbers in the colonic tissue. Their selective depletion by adsorptive granulocyte, monocyte apheresis (GMA), should be therapeutic in patients with UC, although until now efficacy outcomes have been both encouraging and disappointing. The authors' view is that in patients with UC, there is an evolving scope for therapeutic opportunity based on taking away the sources of inflammatory cytokines, also considering the favorable safety profile of GMA.

Granulocytapheresis in steroid-dependent and steroid-resistant patients with inflammatory bowel disease: a prospective observational study.

BACKGROUND: Despite the mounting importance of granulocytapheresis (GCAP) for inflammatory bowel disease (IBD) treatment, its effectiveness in steroid-dependent (SD) and steroid-resistant (SR) patients has not been clearly evaluated. This prospective observational study describes the use of GCAP in SD and SR patients with either Ulcerative Colitis (UC) or Crohn's Disease (CD). METHODS: 118 patients, 83 affected by UC (55 SD and 28 SR) and 35 by CD (22 SD and 13 SR), were treated with GCAP, using Adacolumn™, for 5 consecutive weeks, 1 session/week. All patients were followed for 12 months after the end of GCAP. Clinical remission was defined as Clinical Activity Index (CAI) ≤6 for UC patients and Crohn's Disease Activity Index (CDAI) <150 for CD patients. RESULTS: All patients completed the study; no major complications were reported. At the end of GCAP 71% of UC and 63% of CD patients showed clinical remission. At 6 months the remission was maintained by 66% and 54% of UC and CD patients respectively, while at 12 months the percentages were 48% and 43%, respectively. No differences between SD and SR subgroups were reported at any timepoint. CAI and CDAI values significantly dropped after GCAP treatment and at 6 and 12 months' follow-up (p<0.05 vs baseline for both timepoints). No differences were measured in CAI and CDAI between SD and SR patients. CONCLUSION: GCAP therapy is safe and effective in inducing and maintaining clinical remission both in SD and in SR patients affected by either UC or CD.

Assessment of response to sorafenib in advanced hepatocellular carcinoma using perfusion computed tomography: results of a pilot study.

AIMS: This prospective pilot study investigated the feasibility of perfusion computed tomography parameters as surrogate markers of angiogenesis and early response following sorafenib administration in patients with advanced hepatocellular carcinoma. METHODS: Ten patients were evaluated with perfusion computed tomography before starting sorafenib and after 3 months. Blood flow, blood volume, mean transit time, hepatic arterial fraction, and permeability surface-product were compared in tumour lesions and in hepatic parenchyma at baseline and at follow-up. Correlation between these parameters and changes in alpha-fetoprotein levels was calculated. RESULTS: At baseline, blood volume, blood flow, hepatic arterial fraction and permeability surface values were higher in lesions compared to those in hepatic parenchyma, while mean transit time was lower (p<0.05). After sorafenib treatment, only mean transit time was significantly increased versus baseline (p<0.05). At follow-up, plasma alpha-fetoprotein levels decreased in all patients. At follow-up, an inverse correlation was observed between baseline mean transit time and changes in alpha-fetoprotein (r=-0.6685, p=0.0125), as well as a correlation between baseline blood flow and alpha-fetoprotein (r=0.6476, p=0.0167). CONCLUSION: This pilot study suggests that after sorafenib treatment an increase in mean transit time observed in tumour lesions is inversely correlated with alpha-fetoprotein reductions after therapy. Mean transit time may represent a possible marker of response irrespectively of alpha-fetoprotein values.

Long-term results of sorafenib in advanced-stage hepatocellular carcinoma: what can we learn from routine clinical practice?

BACKGROUND AND AIMS: Prospective randomized trials have proven that sorafenib is a valid treatment option for patients with advanced-stage hepatocellular carcinoma (HCC). The aim of the present study is to evaluate the effectiveness and safety of sorafenib in patients encountered in routine clinical practice. METHODS: From September 2008 to March 2011, 42 cirrhotic patients (30 male; 12 female; mean age: 70.2 ± 7.6 years; range: 56-85 years) with HCC of Barcelona Clinic Liver Cancer stage B (n = 5) or C (n = 37; mean size: 66.6 ± 42.3 mm; mean number per patient: 3.3 ± 2.8) were treated with sorafenib at either a standard dose of 800 mg/day (n = 29; 69.1%) or at 400 mg/day with subsequent dose escalation (ramp-up strategy; n = 13, 30.9%). Baseline clinical parameters were comparable. Clinical data and side effects, laboratory analyses (in particular, serum α-fetoprotein) and radiological data (tumor response according to amended RECIST criteria) were assessed every 3 months. Survival was calculated by Kaplan-Meier analysis. RESULTS: Mean follow-up was 12.2 ± 9 months (range: 1-32 months). Median overall survival was 26.1 months with overall 6- and 12-month survival rates of 92.1 and 85%, respectively. Median time to radiological progression was 8 months. The progression-free rate was 64.3%. Fatigue, skin disorders and diarrhea were the most frequent grade 3-4 side effects. Treatment discontinuation occurred in 25 patients. The starting dose for the last 13 enrolled patients was 400 mg/day; in the absence of toxicity this dosage was gradually increased to 800 mg/day after 3 weeks ('ramp-up strategy'). No grade 3/4 adverse events were observed in the ramp-up group. CONCLUSION: Sorafenib is a valid treatment option for advanced-stage HCC. Starting at a lower dosage may allow prolonged compliance to treatment and might be considered according to patient tolerance.

[Predictors of clinical response in patients with ulcerative colitis treated with granulocyte-monocyte apheresis: analysis of the apheresis registry data]. / Predittori di risposta clinica in pazienti affetti da colite ulcerosa trattati con granulocito-monocito aferesi: analisi dei dati del registro aferesi.

We analyzed predictors of clinical response after a cycle of granulocytemonocyte apheresis in 173 patients with ulcerative colitis. Hemoglobin levels independently predicted good clinical outcome.

Transarterial chemoembolization in very early and early-stage hepatocellular carcinoma patients excluded from curative treatment: a prospective cohort study.

AIM: To assess clinical outcome of transarterial chemoembolization (TACE) in a series of patients with early-stage hepatocellular carcinoma (HCC), within Milan criteria, but clinically unfit for liver transplantation (OLT). METHODS: From January 2006 to May 2009, 67 patients (43 males, mean age 70 ± 7.6 years) with very early or early-stage unresectable HCC, within Milan selection criteria but clinically unfit for OLT, underwent TACE. The primary endpoint of the study was overall survival. Secondary endpoints were: safety, liver toxicity, 1-month tumour response according to the amended RECIST criteria, time to local and distant intrahepatic tumour recurrence and time to radiological progression. RESULTS: Two major periprocedural complications occurred (3%), consisting of liver failure. Periprocedural mortality rate was 1.5% (1 patient). A significant increase in ALT and bilirubin levels 24h after treatment was reported, with progressive decrease at discharge. At 1-month follow-up, complete and partial tumour response rates were 67.2% and 29.8%, respectively, with two cases of progressive disease. Mean follow-up was 37.3 ± 15 months. The 1-, 2-, and 3-year overall survival rates were 90.9%, 86.1%, and 80.5%, respectively. Median expected time to local tumour recurrence and intrahepatic tumour recurrence were 7.9 and 13.8 months, respectively. Radiological disease progression was observed in 12 patients (17.9%) with a mean expected time of 26.5 months. CONCLUSION: In patients with early-stage HCC, clinically excluded from OLT and unfit for surgery or percutaneous ablation, TACE is a safe and effective option, with favourable long-term survival.