Regorafenib Efficacy After Sorafenib in Patients With Recurrent Hepatocellular Carcinoma After Liver Transplantation: A Retrospective Study.

Safety of regorafenib in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) has been recently demonstrated. We aimed to assess the survival benefit of regorafenib compared with best supportive care (BSC) in LT patients after sorafenib discontinuation. This observational multicenter retrospective study included LT patients with HCC recurrence who discontinued first-line sorafenib. Group 1 comprised regorafenib-treated patients, whereas the control group was selected among patients treated with BSC due to unavailability of second-line options at the time of sorafenib discontinuation and who were sorafenib-tolerant progressors (group 2). Primary endpoint was overall survival (OS) of group 1 compared with group 2. Secondary endpoints were safety and OS of sequential treatment with sorafenib + regorafenib/BSC. Among 132 LT patients who discontinued sorafenib included in the study, 81 were sorafenib tolerant: 36 received regorafenib (group 1) and 45 (group 2) received BSC. Overall, 24 (67%) patients died in group 1 and 40 (89%) in group 2: the median OS was significantly longer in group 1 than in group 2 (13.1 versus 5.5 months; P < 0.01). Regorafenib treatment was an independent predictor of reduced mortality (hazard ratio, 0.37; 95% confidence interval [CI], 0.16-0.89; P = 0.02). Median treatment duration with regorafenib was 7.0 (95% CI, 5.5-8.5) months; regorafenib dose was reduced in 22 (61%) patients for adverse events and discontinued for tumor progression in 93% (n = 28). The median OS calculated from sorafenib start was 28.8 months (95% CI, 17.6-40.1) in group 1 versus 15.3 months (95% CI, 8.8-21.7) in group 2 (P < 0.01). Regorafenib is an effective second-line treatment after sorafenib in patients with HCC recurrence after LT.

Switch from intravenous or intramuscular to subcutaneous hepatitis B immunoglobulin: effect on quality of life after liver transplantation.

BACKGROUND: Hepatitis B immunoglobulin (HBIG) therapy is available in intravenous (IV) or intra-muscular (IM) formulations. Recently, a subcutaneous (SC) formulation was introduced. This study evaluated changes in quality of life when liver transplant (LT) recipients were switched from IV or IM HBIG to the SC formulation. METHODS: This multicentre, observational study involved adults who had undergone LT at least 1 year prior to study entry. Quality of life was evaluated using the ITaLi-Q questionnaire, assessing the impact of HBIG therapy on daily activities and patient satisfaction, and the SF-36 Health Survey. Patients completed the questionnaires prior to switching from IV or IM HBIG to SC HBIG and 6 months later. RESULTS: Eighty-six patients were enrolled; before the switch, 68.6% were receiving IM HBIG and 31.4% IV HBIG. After 6 months, significant improvements in 7 of the 8 ITaLi-Q domains were found, particularly side effects, need for support to adhere to the therapy and satisfaction with the HBIG therapy. Significant improvements in several SF-36 domains were documented, including physical functioning, physical and emotional role limitations, pain, social functioning, physical and mental summary scores. CONCLUSIONS: The SC route of administration reduces side effects and their interference with daily life, ameliorates negative feelings, and increases patient autonomy.

Outcomes of Liver Transplant for Adults With Wilson's Disease.

Wilson's disease (WD) is a rare genetic disorder with protean manifestations. Even if liver transplantation (LT) could represent an effective therapeutic option for patients with end-stage liver disease, it has remained controversial in the presence of neuropsychiatric involvement. This study aimed to examine the frequency of adult LT for WD in Italy, focusing on the disease phenotype at the time of LT. A retrospective, observational, multicenter study was conducted across Italy exploring the frequency and characteristics of adults transplanted for WD between 2006 and 2016. A total of 29 adult WD patients underwent LT during the study period at 11 Italian LT centers (accounting for 0.4% of all LTs performed), and 27 of them were considered in this analysis (male/female, n = 9/18; age at LT, 29 years [19-60 years]; median Model for End-Stage Liver Disease score at LT, 27 [6-49]). Isolated hepatic phenotype was the indication for LT in 17 (63%) patients, whereas 2 (7%) patients underwent LT for neurological impairment on compensated liver disease. Overall 1- and 5-year patient survival was excellent (88% and 83%, respectively). Neuropsychiatric symptoms early after LT completely recovered in only a few patients. In conclusion, WD remains an uncommon, unusual indication for LT in Italy, displaying good post-LT graft and patient survival. Because isolated neuropsychiatric involvement represents a rare indication to LT, more data are needed to properly assess the value of LT for WD in this subset of patients.

Experience With Early Sorafenib Treatment With mTOR Inhibitors in Hepatocellular Carcinoma Recurring After Liver Transplantation.

BACKGROUND: Sorafenib (SOR) is currently used for hepatocellular carcinoma (HCC) recurring after liver transplantation (LT) when HCC is unsuitable for surgical/locoregional treatments. We evaluated safety and effectiveness of early introduction of SOR after HCC-recurrence. METHODS: All patients with HCC-recurrence after LT treated with SOR in 2 centers were included (January 2008 to June 2018). Baseline and on-treatment data were collected. RESULTS: Fifty patients early treated with SOR for HCC-recurrence after LT (74% mammalian target of rapamycin inhibitor [mTORi], 54% HCC-treated at baseline) were enrolled. During 7.3 (0.3-88) months of SOR, all patients had at least one adverse event (AE), 56% graded 3-4. SOR was reduced in 68%, being AEs the main cause of reduction, and discontinued in 84% (60% symptomatic progression, 33% AE). Objective response was obtained in 16% and stable disease in 50%. Median time to radiological progression was 6 months (95% confidence Interval [CI], 4-8). Thirty-three patients (69%) died, 94% for HCC progression. Median overall survival (OS) was 18 months (95% CI, 8-27); 5-year OS was 18% (95% CI, 4%-32%). Baseline predictors of OS were SOR+mTORi (hazard ratio [HR], 0.4; 95% CI, 0.2-0.9; P = 0.04), previous curative treatments (HR, 0.3; 95% CI, 0.2-0.7; P = 0.003) and alpha-fetoprotein > 100 ng/mL (HR, 2.5; 95% CI, 1.1-5.0, P = 0.02). At multivariate analysis, HCC curative treatment was the only independent predictor (HR, 0.4; 95% CI 0.2-1.0; P = 0.04). CONCLUSIONS: Early and combined treatment with SOR and mTORi resulted in a favorable safety profile, while its effectiveness should be confirmed by meta-analysis of previous studies or by larger studies. Curative treatment for HCC resulted the only independent predictor of OS.

Efficacy and Tolerability of Direct-Acting Antivirals for Hepatitis C in Older Adults.

OBJECTIVES: To evaluate the efficacy and tolerability of direct-acting antiviral (DAA) therapy in individuals aged 65 and older. DESIGN: Retrospective review between June 2014 and January 2017. SETTING: Viral hepatitis outpatient clinic. PARTICIPANTS: Individuals aged 65 and older treated with DAA therapy for hepatitis C virus (HCV) during the study period (N=113) divided into 2 cohorts: aged 65 to 74 (n=88) and aged 75 and older (n=25). MEASUREMENTS: Drug-drug interactions (DDIs), adverse events (AEs), and rates of sustained virologic response with DAA therapy were assessed. RESULTS: Sustained virologic response rate was 97.7% in individuals aged 65 to 74 and 95.8% in those aged 75 and older. Individuals aged 75 and older were more likely to be taking more than 2 medications per day for chronic conditions (84% vs 62%, p=.02) and more likely to have clinically significant DDIs necessitating cessation or adjustment of medications before commencement of DAA therapy (80% vs 36%, p=.001). Moreover, individuals aged 75 and older were more likely to experience an AE during therapy (50% vs 26%, p=.03) and were more susceptible to developing anemia secondary to ribavirin (60% vs 20%, p=.02). CONCLUSION: DAA therapy is highly efficacious for the treatment of HCV in older adults, but those aged 75 and older are more likely to have clinically significant pretreatment DDIs and experience AEs, including ribavirin-induced anemia, during therapy.

Risk of hepatocellular carcinoma in relation to ABO blood type.

BACKGROUND: Mortality and incidence rates of hepatocellular carcinoma (HCC) parallel the geographical distribution of hepatitis B and C viruses among the general population, however genetic factors modulate individual cancer risk. AIMS: ABO blood type, as a genetic marker, has previously been associated with the risk of several malignancies; we aimed to evaluate whether an association exists with HCC. METHODS: This is a retrospective case-control study based on ABO distribution in 194 patients with HCC, compared with 215 decompensated cirrhotics without HCC listed for liver transplantation, and 90,322 healthy blood donors. RESULTS: In patients with HCC, prevalence of blood type O was 35%, vs. 44% in cirrhotics (OR: 0.67, 95% CI 0.45-0.99; p=0.046) and 45% in blood donors (OR: 0.65, 95% CI 0.48-0.88; p=0.004). CONCLUSIONS: ABO blood type non-O is associated with higher risk of hepatocellular carcinoma, compared to cirrhotics without HCC and healthy subjects.

Transarterial chemoembolization with drug-eluting beads is effective for the maintenance of the Milan-in status in patients with a small hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is the standard of care for the treatment of patients with an intermediate (Barcelona Clinic Liver Cancer [BCLC] B) hepatocellular carcinoma and to bridge patients with an early cancer to liver transplantation (LT). We explored the efficacy of TACE with drug-eluting beads (DEB) in BCLC A patients. Included are all BCLC A patients unsuitable for resection or locoregional ablation who underwent a DEB TACE between 2006 and 2012. Treatment was carried out "a la demande" until complete tumor devascularization or progression beyond Milan criteria. In patients with a complete response (CR), a contrast computed tomography (CT) scan was repeated at 3-month intervals during the first 2 years and then every 6 months alternating with abdominal ultrasound in the subsequent 3 years. Fifty-five patients had 79 tumor nodules ranging 7 to 50 mm; 32 (58%) achieved a CR that was maintained up to 4 and 7 months in 21 (38%) and 17 (31%) patients, respectively. The 24- and 36-month tumor-free survivals were 21% and 9%, respectively. The overall cumulative progression beyond Milan criteria at 3, 6, 12, and 24 months was 2%, 5%, 30%, and 54%. LT eligibility was maintained for a median of 19 months (range, 2-63 months). CR to first TACE was the strongest independent predictor of Milan-in maintenance. In conclusion, DEB TACE may effectively bridge patients with an early cancer to LT, and a CR to the first procedure may guide patient prioritization during the waiting list.

Clinical and economical impact of 2010 AASLD guidelines for the diagnosis of hepatocellular carcinoma.

BACKGROUND & AIMS: Although contrast-enhanced computed tomography (CT), dynamic magnetic resonance (MRI) and fine needle biopsy (FNB) are the standard of care to diagnose hepatocellular carcinoma (HCC), the clinical and economic benefits of the updated AASLD diagnostic algorithm, including the drop of contrast enhanced ultrasound (CEUS), have not been previously evaluated. METHODS: 119 de novo liver nodules detected during ultrasound (US) surveillance in 98 cirrhotics, 7 <1cm, 67 1-2cm, 45 >2cm in size, were sequentially examined by CEUS and CT, using MRI as a rescue approach in patients lacking a typical vascular pattern for HCC by one or both contrast techniques in the 1-2cm nodules and by CT in the >2cm nodules. A FNB was performed when required to meet both 2005 and 2010 AASLD criteria. RESULTS: Eighty-four (70%) nodules were HCC: the radiological diagnosis was done in 38 (88%) of those 1-2cm and in 38 (95%) for those >2cm HCCs according to 2010 AASLD criteria. CT or MRI detected 13 HCC nodules that were missed by unenhanced US. Despite an absolute specificity, CEUS failed to identify any HCC uncharacterized by CT or MRI. By updated AASLD criteria, 6 (17%) FNB procedures were spared in patients with 1-2cm nodules (p=0.025), as compared to 2005 criteria. The 2010 vs. 2005 AASLD per patient cost was similar in 1-2cm nodules, 432 € vs. 451 € (p=0.46), but lower in >2cm nodules, 248 € vs. 321 € (p<0.001). CONCLUSIONS: A sequential study with either CT or MRI enhances the radiological diagnosis of HCC and reduces costs and liver biopsy need.

Early and late de novo tumors after liver transplantation in adults: the late onset of bladder tumors in men.

BACKGROUND: De novo tumors (DNT) after liver transplantation (LT) represent a growing concern. PATIENTS AND METHODS: We analyzed the incidence of DNT, type, time of onset, risk factors and mortality (as of 2010) in 494 adult patients transplanted in the last 26 years (1983-2009). RESULTS: DNT occurred in 41 (8.3%) of the patients. The Standardized Incidence Ratio (SIR) compared with the Italian population was 1.8. There was a higher incidence in males (SIR 2.0), an expected extremely high rate of Kaposi's sarcoma (SIR 127.95) and unexpected higher rates of tumors of the bladder in males (SIR 3.3). The incidence of DNT was higher within the first two years of LT (SIR 2.7) for Kaposi's sarcoma (SIR 393.3) and after 10 years (SIR 1.7) for bladder tumors (SIR 10.6). Multivariate analysis identified alcoholic cirrhosis (HR = 3.0, 95% CI = 1.2-7.8) and sclerosing cholangitis (HR = 3.5, 95% CI = 1.1-11.3) in the recipient as main risk factors for the occurrence of DNT. CONCLUSIONS: Surveillance protocols for DNT must be specifically oriented to patients transplanted for alcoholic cirrhosis and sclerosing cholangitis. They should focus on early detection of Kaposi's sarcomas, and more remarkably, on late development bladder tumors in men after LT.

Contrast-enhanced computed tomography and ultrasound-guided liver biopsy to diagnose dysplastic liver nodules in cirrhosis.

BACKGROUND: Dysplastic nodules in cirrhosis herald a very high risk of transition to hepatocellular carcinoma. A better understanding of the relationships between dysplastic nodules and hepatocellular carcinoma development may help refining strategies of enhanced follow-up. METHODS: All consecutive cirrhotics with a histologically proven de novo dysplastic nodule, were retrospectively identified and underwent alternating abdominal ultrasound and contrast-computed tomography every 3 months. An ultrasound-guided liver biopsy was the diagnostic gold standard, whereas surveillance and recall policies were according to current guidelines. RESULTS: Among 36 patients with dysplastic nodule (21 low-grade, 15 high-grade, 17.4 ± 2.6mm), 17 (47%) showed arterial wash-in, 15 (42%) portal/venous hypodensity whereas 4 (11%) had neither pattern. During 6-128 (median 36) months, 21 patients developed a hepatocellular carcinoma at a rate of 13.8% per year, intranodular=8.7% vs extranodular=7.1% per year. Hepatocellular carcinoma occurred more frequently in high-grade than low-grade dysplastic nodules (32.2% vs 9.3% per year, p=0.0039); the maximum time to hepatocellular carcinoma transformation was 27 months for intranodular vs 67 months for extranodular tumours (p=0.025). No contrast-computed tomography pattern predicted neoplastic transformation of dysplastic nodules. CONCLUSION: The histological examination of liver nodules in cirrhosis lacking the imaging hallmark of hepatocellular carcinoma improves both prognostication and outcome of surveillance, since it dictates the intensity of the radiological follow-up.