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Background and Aims: Hepatocellular carcinoma (HCC) is a significant public health issue, with an increasing incidence and prevalence and a high incidence-to-mortality ratio. The prognosis of HCC depends on two competing factors, tumor burden and underlying liver disease severity, encompassed in the Barcelona Clinic Liver Cancer (BCLC) classification. To assess HCC staging and the way staging affects eligibility for treatment at the time of the first diagnosis in Romania in the setting of opportunistic diagnosis, in the absence of a national HCC screening policy., Methods: Data regarding HCC staging, underlying liver disease, and eligibility for treatment at the time of diagnosis was analyzed using a prospectively maintained multicentric database, which included patients from the five largest tertiary care hepatology units in the country between June 2016 and February 2020., Results: A consecutive series of 477 patients was included. The distribution within BCLC classes was as follows: very early (0) 7.1%, early (A) 34.3%, intermediate (B) 19.4%, advanced (C) 14.2%, terminal (D) 24.7%. At the time of the diagnosis, 198 (41.5%) were eligible for a curative intent treatment, while 359 (75.2%) were eligible for a disease-modifying therapy. 228 patients (47.8%) had decompensated liver disease at the time of diagnosis, the most common decompensating event being ascites (78.1%)., Conclusions: A large proportion of HCC cases are diagnosed at the time of a decompensating event, severely restricting the therapeutic potential. Proactive diagnostic strategies should be implemented to improve the rate of actionable diagnosis.

Background and Aims: The sofosbuvir (SOF) / velpatasvir (VEL) / voxilaprevir (VOX) combination has been evaluated in more than 800 patients enrolled in phase II and phase III studies, where it demonstrated excellent safety and efficacy, achieving overall sustained viral response (SVR) rates of more than 95%. We aimed to assess the efficacy and safety of SOF/VEL/VOX in a real-world study, including patients previously treated for genotype 1b hepatitis C virus (HCV) infection that did not obtain a sustained viral response with previous direct-acting antivirals (DAAs) therapy., Methods: In Romania, through a nationwide government-funded program in 2019-2020, 213 patients with chronic hepatitis C non-responders to previous DAAs therapy, received treatment with SOF/VEL/ VOX 400/100/100 mg/day for 12 weeks. We performed a retrospective longitudinal study that included 143 individuals who were treated in Bucharest, Iași, Craiova and Constanța clinics, all with genotype 1b HCV infection. Efficacy was assessed by the percentage of patients achieving SVR 12 weeks post-treatment (SVR12). Serious adverse events (SAE) were registered., Results: Our cohort comprised 53% males with a median age of 60 years (27÷77); 47% were pre-treated with ombitasvir/paritaprevir/ritonavir+dasabuvir ± ribavirin, 40% with ledipasvir/SOF, 13% with elbasvir/ grazoprevir. 42% of patients associated co-morbidities, 45% had compensated liver cirrhosis, 2% had treated hepatocellular carcinoma (HCC) and 1% had hepatitis B virus co-infection. SVR by intention to treat was reported in 139/143 (97.2%) and per protocol in 141/143 (98.6%). No predictive factors for SVR were identified. Rate of liver decompensation in patients with cirrhosis was 6% and was statistically associated in multivariate analysis with Child-Pugh score (p<0.01) and with severe steatosis (p=0.004). Occurrence of new HCC was reported in 3.6% of all patients with cirrhosis and was associated with poor liver function [higher Child-Pugh score (p=0.001) and low albumin levels (p=0.02)]. Serious adverse events related to therapy were reported in 1/143(0.7%)., Conclusions: SOF/VEL/VOX was highly efficient in our population of patients with a 97.2% SVR. Liver decompensation occurred in 6% of cirrhotic patients at SVR, related to hepatic dysfunction.

Background and Aims: Differences between countries in NAFLD patient care pathways and management need to be understood prior to defining supranational guidelines., Approach and Results: We conducted an anonymous survey in France, Germany, Hong Kong, Italy, Romania, Spain, the United Kingdom, and the United States among physicians providing specialist care for patients with NAFLD. Modalities of patient referral, patterns of practice (diagnosis, staging, monitoring, and indications for liver biopsy), therapeutic management, and expectations for future NASH pharmacotherapies were assessed, with 664 physicians completing the survey. Referral to surveyed physicians (SPs) mostly came from primary care. Prior to referral, NAFLD was rarely diagnosed, and noninvasive tests were not performed. Screening for comorbidities by SPs was incomplete and cardiovascular risk not calculated. Elastometry in combination with a serum biomarker was the most common first-line method for fibrosis staging. Liver biopsy, when performed, was often delayed by at least 1 year after diagnosis. It was, however, recommended even if noninvasive methods indicated advanced fibrosis. Frequent, biannual monitoring was conducted, including HCC surveillance in Stage 3 fibrosis. SPs rarely implemented and followed dietary and lifestyle changes themselves, and local availability of such programs was highly heterogenous. SPs favored pharmacotherapy based on mechanism of action adapted to the stage of the disease, including for early stages such as steatohepatitis with mild fibrosis., Conclusions: This international survey revealed major deficiencies and delays in referral pathways, suboptimal screening for comorbidities or managing of lifestyle modifications by SPs, and limited local availability for nonpharmacological interventions. Monitoring practices are not aligned with current guidelines., (© 2022 American Association for the Study of Liver Diseases.)

Background and Aims: We assessed the clinical and economic impact of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) in England, Italy, Romania and Spain., Methods: An HCV progression Markov model was developed considering DAA eligibility and population data during the years 2015-2019. The period of time to recover the investment in DAAs was calculated as the cost saved by avoiding estimated clinical events for 1000 standardized treated patients. A delayed treatment scenario because of coronavirus disease (COVID-19) was also developed., Results: The estimated number of avoided hepatocellular carcinoma, decompensated cirrhosis and liver transplantations over a 20-year time horizon was: 1,057 in England; 1,221 in Italy; 1,211 in Romania; and 1,103 in Spain for patients treated during 2015-2016 and 640 in England; 626 in Italy; 739 in Romania; and 643 in Spain for patients treated during 2017-2019. The cost-savings ranged from € 45 to € 275 million. The investment needed to expand access to DAAs in 2015-2019 is estimated to be recovered in 6.5 years in England; 5.4 years in Italy; 6.7 years in Romania; and 4.5 years in Spain. A delay in treatment because of COVID-19 will increase liver mortality in all countries., Conclusion: Direct-acting antivirals have significant clinical benefits and can bring substantial cost-savings over the next 20 years, reaching a Break-even point in a short period of time. When pursuing an exit strategy from strict lockdown measures for COVID-19, providing DAAs should remain high on the list of priorities in order to maintain HCV elimination efforts., (© The Authors. Liver International published by John Wiley & Sons Ltd.)

Background and Aims: To evaluate the predictive factors for recurrence of the disease and overall survival (OS) after achieving complete response (CR) in patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE)., Methods: From January 2013 to December 2017, 168 treatment-naïve patients diagnosed with HCC underwent TACE as a first-line therapy and the gathered data was retrospectively reviewed. We determined the predictive factors for complete response (CR), for recurrence after CR and for survival using the Cox proportional hazard model., Results: Median follow-up was 27.4 months (range 4-65 months). The mean patient age was 62.2+/-7.9 years. Eighty-three patients had an α-fetoprotein (AFP) level > 20ng/mL. The median maximal diameter of the tumors was 3.5 cm. Sixty-three patients (37.5%) achieved CR after TACE, and recurrence after CR was detected in 37 patients (58.7%). In multivariate analysis, tumor size ( 25 ng/mL and multiple tumors were demonstrated to have a significant relationship with recurrence after CR, with HRs of 1.650 (p=0.05) and 3.932 (p=0.038), respectively. Increased initial serum AFP > 22 ng/mL, tumor size > 4.5 cm, outside Milan criteria, not receiving a liver transplant and presence of portal vein thrombosis (PVT) were correlated with poor survival., Conclusions: In patients treated with TACE as an initial therapy, tumor size (≤4.5 cm) and single tumor were predictive factors for CR. Multiple nodules and an elevated serum AFP > 25 ng/mL were predictive factors for recurrence after CR. Outside Milan criteria tumors, elevated AFP levels and the presence of PVT were significantly correlated with decreased survival.

Background: The objective of this study is to assess the outcome of the patients treated for hepatocellular carcinoma (HCC) in a General Surgery and Liver Transplantation Center. Methods: This retrospective study includes 844 patients diagnosed with HCC and surgically treated with curative intent methods. Curative intent treatment is mainly based on surgery, consisting of liver resection (LR), liver transplantation (LT). Tumor ablation could become the choice of treatment in HCC cases not manageable for surgery (LT or LR). 518 patients underwent LR, 162 patients benefited from LT and in 164 patients radiofrequency ablation (RFA) was performed. 615 patients (73%) presented liver cirrhosis. Results: Mordidity rates of patient treated for HCC was 30% and mortality was 4,3% for the entire study population. Five year overall survival rate was 39 % with statistically significant differences between transplanted, resected, or ablated patients (p 0.05) with better results in case of LT followed by LR and RFA. Conclusions: In HCC patients without liver cirrhosis, liver resection is the treatment of choice. For early HCC occurred on cirrhosis, LT offers the best outcome in terms of overall and disease free survival. RFA colud be a curative method for HCC patients not amenable for LT of LR., (Celsius.)

We present the case of a previously healthy 62 year old man who developed primary non-Hodgkin lymphoma of the liver. Biopsy confirmed that it was a diffuse large anaplastic T-cell lymphoma of an extremely rare type. The diagnosis of this type of lesions is suggested by the presence of a hepatic mass without lymphadenopathy, splenomegaly or bone marrow involvement associated with normal tumor markers (carcinoembryonic antigen, alpha-fetoprotein and CA 19-9 levels). Histological examination of tissue is essential to confirm the diagnosis. Treatment options are surgical resection and/or chemotherapy but the rate of response to treatment varies widely. Some patients can achieve prolonged remission.

Background: Small nodules (under 3 cm) detected on ultrasound (US) in cirrhotics represent the most challenging category for noninvasive diagnosis of hepatocellular carcinoma (HCC)., Aim: To evaluate real-time sonoelastography as a noninvasive tool for the diagnosis of small HCC nodules in cirrhotic patients., Methods: 42 cirrhotic patients with 58 nodules (1-3 cm) were evaluated with real-time elastography (Hitachi EUB-6500); the mean intensity of colors red, blue, green were measured using a semi-quantitative method. Analysis of histograms for each color of the sonoelastography images was performed for quantifying the elasticity of nodule tissue in comparison with the cirrhotic liver tissue. AUROC curves were constructed to define the best cut-off points to distinguish malignant features of the nodules. Univariate and multivariate logistic regression analysis was performed., Results: 595 sonoelastography images from 42 patients (25 men; 17 women) were analyzed. The mean age was 56.4 +/- 0.7 years and 69% patients were in Child-Pugh class A, 19% class B, 11% class C. For the mean intensity of green color AUROC=0.81, a cut-off value under 108.7 being diagnostic for HCC with a Sp=91.1%, Se=50%, PPV=92.1%, NPV=47.1%. Mean intensity of blue color proved to be an excellent diagnostic tool for HCC (AUROC=0.94); for a cut-off value greater than 128.9, Sp=92.2%, Se=78.9%, PPV=95.4%, NPV=68%. Independent predictive factors of HCC for a small nodule in cirrhotic patients were: blue color over 128.9 at sonoelastography and hypervascular appearance at Doppler US., Conclusions: US elastography is a promising method for the non-invasive diagnosis of early HCC. Blue color at elastography and hypervascular aspects are independent predictors of HCC.

A 46-yr-old female with hepatocellular carcinoma and severe hepatitis B-related liver cirrhosis received a domino liver graft from a 25-yr-old female with homozygous familial hypercholesterolemia (HFHC) in September 2001. Hypercholesterolemia occurred in the graft recipient within one yr after transplantation and was partially controlled by atorvastatin. Three yr after transplantation, an autologous CD34(+) cell transplantation was performed in order to better control the hypercholesterolemia. Only preliminary results of this domino liver transplantation (DLT) were published in 2003, without a long-term analysis of the hypercholesterolemic effects in recipient. Subsequent to DLT, the average plasma cholesterol level in the domino donor rapidly normalized and seven yr after had a value of 182 mg/dL. After seven-yr follow-up, the domino recipient has no hepatocarcinoma recurrence. Moreover, no signs of cardiovascular or atherosclerotic lesions were noted despite an elevated plasma cholesterol level (339 mg/dL after seven yr of follow-up) resistant to drug therapy and stem cell autotransplantation. In conclusion, DLT using a liver graft from a patient with HFHC provides a viable option for marginal recipients.

Ultrasound elastography is a new imaging technique that allows a noninvasive estimation and imaging of tissue elasticity distribution within biological tissues using conventional real-time ultrasound equipment with modified software. Elastography has been reported to be useful for differentiation and characterization of various malignant tumors, such as breast, prostate, thyroid, pancreas, lymph nodes, gastrointestinal stromal tumors, hepatocellular carcinoma and liver metastasis. Transient and, more recently, real-time elastography has been proved to be useful for noninvasive assessment of liver fibrosis in patients with diffuse liver diseases. Elasticity imaging promises to make an important contribution to ultrasound practice.

State-of-the-art magnetic resonance (MR) imaging using tissue specific contrast media facilitates detection and characterization in most cases of hepatic nodules. According to the currently used nomenclature, in liver cirrhosis there are only two major types of hepatocellular nodular lesions: regenerative lesions and dysplastic or neoplastic lesions. The purpose of this clinical imaging review is to provide information on the properties of tissue-specific MR contrast agents and on their usefulness in the demonstration of the pathologic changes that take place at the level of the hepatobiliary and reticuloendothelial systems during the carcinogenesis in liver cirrhosis.

We analyze a 123-cases experience over a 5-year period in the treatment of hepatocellular carcinoma (HCC). Liver resection, transplantation and hyperthermic ablation of the tumor were used according to the indication and patient selection. Systemic chemotherapy followed resection in 18 cases and hyperthermic ablation in 5 cases. Chemo-embolisation was performed in patients to be transplanted and in other two patients with tumor destruction. A number of 86 liver resections were performed in 84 patients (2 re- resections in 1 patient, subsequently transplanted) - 43 on normal liver and 41 on cirrhotic liver. Postoperative mortality was 4.7% in non-cirrhotic and 4.9% in cirrhotic patients. Survival in non-cirrhotic patients was 77% at 1 year, 65% at 2 years, and constant - 45% at 3 and 4 years, whereas in cirrhotic patients it was 60%, 56%, 56% and 36% (Kaplan-Meyer actuarial survival rates). Nine patients underwent liver transplantation (4 OLTs, 3 living donor LT, 1 split LT and 1 "domino" LT); postoperative mortality was 11% (1 patient). At present five patients are alive and well. One patient died by peritoneal carcinomatosis at 10 months; another patient died at 6 months by severe cholestatic recurrent C virus hepatitis and one patient was discharged with permanent severe neurologic disturbances. In 31 patients hyperthermic ablation of the tumor was used with zero mortality. Actuarial survival rates were 75% at one year and 67% at 2 years. In conclusion, in non-cirrhotic patients with HCC resection is the treatment of choice. In cirrhotic patients limited resections should be preferred and liver transplantation is the best solution in selected cases; local ablative methods may be used for some unresectable tumors. The role of adjuvant chemotherapy has to be determined in future comparative studies.

The risk of hepatocellular carcinoma superimposed in the evolution of autoimmune hepatitis or primary biliary cirrhosis is low, even in patients with long-standing cirrhosis. We report a case of hepatocellular carcinoma occurring in a 46 year old woman with liver cirrhosis following overlap syndrome between autoimmune hepatitis and primary biliary cirrhosis, routinely followed while on the waiting list for liver transplantation. The patient had combined biochemical (elevated aminotransferases, alkaline phosphatase and gamma-glutamyl-transpeptidase in the range of 2-3 times above the upper limit of the normal) and serological (anti-smooth muscle antibody > 1/80 and anti-mitochondrial antibody anti-M2 > 1/40) criteria of autoimmune hepatitis and primary biliary cirrhosis. Hepatocellular carcinoma was diagnosed in the setting of chronic liver disease by the combination of two concordant imaging technics (Doppler ultrasound and magnetic resonance imaging) showing a hepatic nodule with arterial hypervascularization and elevated serum levels of alpha-fetoprotein up to 950 ng/ml. Liver transplantation is the best treatment both for the solitary nodule less than 5 cm and underlying autoimmune cirrhosis. Using the new Model for End-Stage Liver Disease allocation system our patient was placed in a prior position for liver transplantation (MELD 29). Unfortunately, a sudden fulminant liver failure complicated with intravascular disseminated coagulopathy was fatal for our patient while awaiting liver transplantation.

Background: Domino liver transplantation is one possibility to overcome the discrepancy between the small number of liver donors and the long waiting lists. Homozygous familial hypercholesterolemia (FHC) is a genetic disorder of lipoprotein metabolism defined by the absence or small number of functional low-density lipoprotein receptors (LDL-Rs) and the ensuing high levels of serum cholesterol. We report a case of a patient with FHC whose liver was used for domino transplantation in a patient with cirrhosis and hepatocellular carcinoma., Methods: The patient diagnosed with FHC received the large part of a split liver. The liver of the patient with FHC was then transplanted into the patient with cirrhosis and hepatocellular carcinoma. Quantification of extrahepatic LDL-R was performed by flow cytometry on monocytes, and the gene expression of LDL-R was assayed by reverse transcriptase-polymerase chain reaction on monocyte-derived macrophages and cultured fibroblasts isolated from the patients., Results: One year after surgery, the donor's serum cholesterol (without treatment) was normal, and the recipient's serum cholesterol (with simvastatin treatment) was slightly increased. Quantification of peripheral LDL-R on monocytes isolated from the patients revealed values of 6.7% in the patient with FHC and 71% in the patient with cirrhosis and hepatocellular carcinoma. The reverse transcriptase-polymerase chain reaction assay revealed the presence of gene expression for LDL-R., Conclusions: Domino transplantation can be efficiently used in a patient with marginal indications for transplantation using a liver from a patient with FHC. The slightly elevated serum cholesterol level in the recipient may be explained by the normal function of extrahepatic LDL-R.

Carcinoid tumours are enigmatic, slow growing malignancies, which occur most frequently (74%) in the gastrointestinal tract. Symptoms of the carcinoid syndrome (flushing and diarrhoea) are infrequent, occurring in approximately 10% of the patients with small bowel carcinoid. A 45-year-old patient with multiple liver metastases, diagnosed in 1994 with nonHodgkin's lymphoma after undergoing surgery for a distal ileal tumour, was referred to us by the Department of Haematology. At that moment the issue of a differential diagnosis with a carcinoid tumour arose, due to the long evolution and lack of evidence to support the initial diagnosis. The carcinoid syndrome was in fact present (the patient experiencing flush after small amounts of alcohol and emotions) and also we identified elevated values of 5HIAA. Reevaluation of the histologic sections of the ileal tumour as well as an ultrasound guided fine needle aspiration of an intrahepatic lesion confirmed the diagnosis of "carcinoid tumour". This conclusion lead to new therapeutic options for this patient. One of the main therapeutic options used in treating multiple liver metastases from a carcinoid tumour is chemoembolization and this case offered an excellent opportunity to present this therapy.