Transjugular Intrahepatic Portosystemic Shunt in Nonmalignant Noncirrhotic Portal Vein Thrombosis and Portosinusoidal Vascular Disorder.

Transjugular intrahepatic portosystemic shunt (TIPS) emerges as a key treatment for portal hypertension (PH) complications. While international guidelines provide clear indications for its use in cirrhosis, empirical knowledge is notably scarcer in non-cirrhotic PH, particularly in nonmalignant noncirrhotic portal vein thrombosis (NNPVT) and in patients with portosinusoidal vascular disorder (PSVD). Patients afflicted by these rare diseases exhibit distinct clinical profiles compared to their cirrhotic counterparts, often characterized by a younger age, predominantly preserved hepatic functionality even in cases of severe PH, and a higher propensity for extensive splanchnic thrombosis, which intricately complicates TIPS placement, posing unique challenges for its creation. The objective of this review is to synthesize existing literature on the effectiveness, safety, specific indications, and clinical outcomes of TIPS in adult patients with NNPVT or PSVD, focusing also on the technical challenges of TIPS insertion in the presence of portal cavernoma.

Role of sex in liver tumor occurrence and clinical outcomes: A comprehensive review.

Clinical research on sex-based differences in the manifestations, pathophysiology, and prevalence of several diseases, including those affecting the liver, has expanded considerably in recent years. Increasing evidence suggests that liver diseases develop, progress, and respond to treatment differently depending on the sex. These observations support the concept that the liver is a sexually dimorphic organ in which estrogen and androgen receptors are present, which results in disparities between men and women in liver gene expression patterns, immune responses, and the progression of liver damage, including the propensity to develop liver malignancies. Sex hormones play protective or deleterious roles depending on the patient's sex, the severity of the underlying disease, and the nature of precipitating factors. Moreover, obesity, alcohol consumption, and active smoking, as well as social determinants of liver diseases leading to sex-related inequalities, may interact strongly with hormone-related mechanisms of liver damage. Drug-induced liver injury, viral hepatitis, and metabolic liver diseases are influenced by the status of sex hormones. Available data on the roles of sex hormones and gender differences in liver tumor occurrence and clinical outcomes are conflicting. Here, we critically review the main gender-based differences in the molecular mechanisms associated with liver carcinogenesis and the prevalence, prognosis, and treatment of primary and metastatic liver tumors.

Role of nonneoplastic PVT in the natural history of patients with cirrhosis and first diagnosis of HCC.

BACKGROUND AND AIMS: HCC can increase the risk of nonneoplastic PVT in cirrhosis. However, the natural history of PVT and its prognostic role in HCC patients are unknown. APPROACH AND RESULTS: Consecutive HCC patients with cirrhosis undergoing laparoscopic ablation were retrospectively evaluated and followed up to 36 months. HCC and PVT characteristics and evolution were reviewed. PVT was categorized according to lumen occupancy (≤50%, >50% <100%, and = 100%) and extension to other veins. The evolution of thrombosis was considered at 1 year from diagnosis. Variables associated with the presence of PVT and evolution patterns were analyzed, as well as their impact on survival. In all, 750 patients were included, 88 of whom had PVT. On multivariate analysis, the occurrence of PVT at HCC diagnosis was associated with pretreatment total tumor volume ( p < 0.001) and clinically significant portal hypertension ( p = 0.005). During the follow-up, 46 de novo PVT occurred, 27/46 (58.7%) in the presence of a viable tumor. Among 115 PVT diagnosed in the presence of HCC, 83 had available radiological follow-up, and 22 were anticoagulated. The "complete/progressive" evolution pattern was associated with nonresponse to HCC treatment in non-anticoagulated patients. The presence of PVT was independently associated with lower overall survival, particularly when progressive or occlusive ( p < 0.001). A higher competing risk of death emerged for "complete and progressive" PVT, both for HCC-related ( p < 0.001) and non-HCC-related ( p = 0.002) death. CONCLUSIONS: HCC represents an independent risk factor for the occurrence and progression of PVT in cirrhosis. Since progressive and occlusive PVT seems to be an independent factor associated with mortality, screening and prompt treatment of this complication should be considered.

Global hemostatic profiling in patients with decompensated cirrhosis and bacterial infections.

Background & Aims: Bacterial infections in cirrhosis are associated with increased bleeding risk. To assess the factors responsible for bleeding tendency in patients with bacterial infections, we conducted a prospective study comparing all 3 aspects of hemostasis (platelets, coagulation, and fibrinolysis) in hospitalized patients with decompensated cirrhosis with vs. without bacterial infections. Methods: Primary hemostasis assessment included whole blood platelet aggregation and von Willebrand factor (VWF). Coagulation assessment included procoagulant factors (fibrinogen, factor II, V, VII, VIII, IX, X, XI, XII, XIII), natural anticoagulants (protein C, protein S, antithrombin) and thrombomodulin-modified thrombin generation test. Fibrinolysis assessment included fibrinolytic factors (plasminogen, t-PA, PAI-1, α2-AP, TAFIa/ai) and plasmin-antiplasmin complex (PAP). Results: Eighty patients with decompensated cirrhosis were included (40 with and 40 without bacterial infections). Severity of cirrhosis and platelet count were comparable between groups. At baseline, patients with cirrhosis and bacterial infections had significantly lower whole blood platelet aggregation, without significant differences in VWF. Regarding coagulation, bacterial infections were associated with reduced procoagulant factors VII and XII, and a significant reduction of all natural anticoagulants. However, thrombomodulin-modified thrombin generation was comparable between the study groups. Finally, although mixed potentially hypo-fibrinolytic (lower plasminogen) and hyper-fibrinolytic (higher t-PA) changes were present in bacterial infections, a comparable level of PAP was detected in both groups. Upon resolution of infection (n = 29/40), platelet aggregation further deteriorated whereas coagulation and fibrinolysis factors returned to levels observed in patients without bacterial infections. Conclusion: In hospitalized patients with decompensated cirrhosis, bacterial infections are associated with reduced whole blood platelet aggregation and a significant decrease of all natural anticoagulants, which may unbalance hemostasis and potentially increase the risk of both bleeding and thrombosis. Lay summary: Bacterial infections are a common issue in hospitalized patients with decompensated cirrhosis (i.e. patients hospitalized due to severe complications of advanced chronic liver disease). Patients with decompensated cirrhosis who acquire infections may be at increased risk of bleeding complications following invasive procedures (that is a procedure in which the body is penetrated or entered, for instance by a needle or a tube). As bleeding complications in decompensated cirrhosis are associated with a high risk of further decompensation and death, there is an urgent need to understand the factors responsible for such increased bleeding tendency. Herein, we investigated the alterations of hemostasis (that is the physiological process responsible for clot formation and stability) in patients with decompensated cirrhosis and bacterial infections. We found that development of bacterial infections in these patients is associated with alterations of hemostasis (particularly of platelets and clotting cascade) that may increase the risk of both bleeding and thrombotic complications.

Immune Activation, Exhaustion and Senescence Profiles as Possible Predictors of Cancer in Liver Transplanted Patients.

Liver transplanted (LT) patients for hepatocellular carcinoma (LT-HCC) or for other causes (LT-no-HCC) may develop post-transplantation malignancies. Although immune activation and senescence are frequently implicated in cancer development, no data is available on their possible role as biomarkers predictive of tumor onset in this setting. A total of 116 patients were investigated: the 45 LT-HCC patients were older than the 71 LT-non-HCC (p=0.011), but comparable for sex, HCV, HBV infection and immunosuppressive treatment. At baseline, the numbers of activated and senescent-like circulating cells were significantly higher in LT-HCC patients than in LT-no-HCC ones. After a median follow-up of 26.8 months, 6 post-transplant malignancies (PTM) occurred: 4 in LT-HCC (8.9%) and 2 in LT-no-HCC (2.8%) patients. Overall, subjects with high percentages of activated and exhausted T and B cells at baseline were at higher risk of PTM. Notably, within the LT-HCC group, a higher percentage of senescence-like T cells was also associated with cancer development. Moreover, patients with PTM had higher telomere erosion and higher levels of circulating PAMPs (16S rDNA) and DAMPs (mtDNA) when compared with matched patients without PTM. Overall, these findings suggest that immune activation and exhaustion may be useful to predict the risk of PTM occurrence, regardless of the cause of transplantation. In LT-HCC, T-cell senescence represents an additional risk factor for tumor onset.

Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: an individual patient data meta-analysis.

OBJECTIVE: The benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration. DESIGN: We pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson. RESULTS: Recurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I2=74.6%) and 5.7 (2.5 to 15.3, I2=54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p<0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p<0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1). CONCLUSION: Effects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified.

An Essential Guide for Managing Post-Liver Transplant Patients: What Primary Care Physicians Should Know.

With long-term survival after liver transplantation becoming the rule, care for medical problems arising over time in liver-transplanted patients gained increasing importance. The most common causes of death occurring more than 1 year after liver transplantation are unrelated to liver diseases and facilitated by immunosuppressive treatments; examples are malignancies, renal failure, and cardiovascular, metabolic, and infectious diseases. Recipients receive life-long follow-up care at transplant centers, however, the increasing number of liver-transplanted patients is saturating the health care supply that transplant centers have to offer. Primary care physicians are increasingly exposed to liver-transplanted patients, even in the early periods after transplant, and an understanding of the most common risks and complications faced by these patients would enhance their care. This article reviews the long-term care of liver transplant recipients, emphasizing the key internal medicine-related issues that should be known by primary care physicians. A specific section is devoted to implementing strategies to involve these physicians in the long-term follow-up of liver-transplanted patients in close collaboration with transplant hepatologists.

More Pronounced Hypercoagulable State and Hypofibrinolysis in Patients With Cirrhosis With Versus Without HCC.

In patients with cirrhosis, particularly those with hepatocellular carcinoma (HCC), hypercoagulability may be associated with purported increased risks of portal vein thrombosis and cirrhosis progression. In this study, we extensively investigated hemostatic alterations potentially responsible for the thrombotic tendency in HCC, and evaluated whether such alterations were predictive of hepatic decompensation. Patients with cirrhosis at all stages were prospectively recruited and underwent an extensive hemostatic assessment, including all procoagulant factors and inhibitors, thrombin generation with and without thrombomodulin (TG), profibrinolytic and antifibrinolytic factors, and plasmin-antiplasmin complex. In study part 1 (case control), we compared alterations of coagulation and fibrinolysis in patients with cirrhosis with versus without HCC. In study part 2 (prospective), the subgroup of patients with decompensated cirrhosis was followed for development of further decompensation, and predictors of outcome were assessed by multivariate analysis. One-hundred patients were recruited (50 each with and without HCC). Severity of cirrhosis was comparable between groups. Median HCC volume was 9 cm3 (range: 5-16). Compared with controls, patients with HCC demonstrated a significantly more prothrombotic hemostatic profile due to increased TG and reduced activation of fibrinolysis, independent of cirrhosis stage. During a median follow-up of 175 days, 20 patients with decompensated cirrhosis developed further episodes of decompensation that were predicted by low FVII and high plasminogen activator inhibitor-1 levels, independent of Model for End-Stage Liver Disease score. Conclusion: Patients with cirrhosis with HCC have profound hyper-coagulable changes that can account for their increased thrombotic tendency. In contrast, hypercoagulability in patients with decompensated cirrhosis is more likely a consequence of chronic liver disease rather than a driver for cirrhosis progression.

New Indications for Liver Transplantation.

Liver transplantation (LT) is an important therapeutic option for the treatment of several liver diseases. Modern LT is characterized by remarkable improvements in post-transplant patient survival, graft survival, and quality of life. Thanks to these great improvements, indications for LT are expanding. Nowadays, clinical conditions historically considered exclusion criteria for LT, have been considered new indications for LT, showing survival advantages for patients. In this review, we provide an updated overview of the principal newer indications for LT, with particular attention to alcoholic hepatitis, acute-on-chronic liver failure (ACLF), cholangiocarcinoma and colorectal cancer metastases.

Influence of Hepatocellular Carcinoma on Platelet Aggregation in Cirrhosis.

Hyper-functional platelets are being proposed as a potential therapeutic target in multiple cancers. Whether this can be considered in patients with cirrhosis and hepatocellular carcinoma (HCC) is unknown as their platelet function has not yet been investigated. We evaluated platelet function in cirrhosis patients with HCC. Patients with cirrhosis with and without HCC were prospectively recruited. Platelet aggregation, a marker of platelet function, was assessed by impedance aggregometry with adenosine diphosphate (ADP), arachidonic acid (ASPI), and thrombin (TRAP) stimulation. Plasmatic levels of Von Willebrand factor antigen (VWF) were also determined. One-hundred patients were recruited (50 cirrhotics with and 50 without HCC). Cirrhosis severity by Child class and platelet count were comparable between cirrhotics with and without HCC. Cirrhotics with HCC had higher ADP- (45 vs. 28; p < 0.001), ASPI- (47 vs. 28; p < 0.001), and TRAP- (85 vs. 75; p = 0.01) induced platelet aggregation than cirrhotics without HCC, all indicative of platelet hyper-function. The relatively increased platelet aggregation in patients with HCC was confirmed after adjusting the analysis for platelet count/severity of thrombocytopenia. Levels of VWF were higher in patients with vs. without HCC (348 vs. 267; p = 0.006), particularly in compensated cirrhosis. In patients with cirrhosis, HCC is associated with increased platelet aggregation and higher VWF. The clinical implications of these findings deserve further investigation.

Hepatocellular carcinoma and the risk of de novo malignancies after liver transplantation - a multicenter cohort study.

Patients with hepatocellular carcinoma (HCC) are at high risk of second primary malignancies. As HCC has become the leading indication of liver transplant (LT), the aim of this study was to investigate whether the presence of HCC before LT could influence the onset of de novo malignancies (DNM). A cohort study was conducted on 2653 LT recipients. Hazard ratios (HR) of DNM development for patients transplanted for HCC (HCC patients) were compared with those of patients without any previous malignancy (non-HCC patients). All models were adjusted for sex, age, calendar year at transplant, and liver disease etiology. Throughout 17 903 person-years, 6.6% of HCC patients and 7.4% of non-HCC patients developed DNM (202 cases). The median time from LT to first DNM diagnosis was shorter for solid tumors in HCC patients (2.7 vs 4.5 years for HCC and non-HCC patients, respectively, P < 0.01). HCC patients were at a higher risk of bladder cancer and skin melanoma. There were no differences in cumulative DNM-specific mortality by HCC status. This study suggests that primary HCC could be a risk factor for DNM in LT recipients, allowing for risk stratification and screening individualization.

Current and future perspective on targeted agents and immunotherapies in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related death worldwide. HCC occurs predominantly in patients with underlying chronic liver disease and cirrhosis, and it presents a poor prognosis in advanced stage. Since its approval, for the following 10 years, sorafenib remained the only systemic agent with proven clinical efficacy for patients with advanced HCC. Recently, more drugs have been studied and several advances in first­line and second­line treatment options should yield significant improvements in survival. Lenvatinib, another tyrosine­kinase inhibitor, was found to be non-inferior to sorafenib in terms of overall survival (OS), with significantly better progression-free survival and objective response rate (ORR). The tyrosinekinase inhibitors, regorafenib and cabozantinib, were shown to significantly improve survival in the second­line setting after sorafenib failure. Ramucirumab, a VEGF inhibitor, can also improve survival in the second­line setting among patients with AFP≥400 ng/dL. Moreover, good efficacy was seen in phase I/II trials of immune checkpoint inhibitors as monotherapy. Ongoing trials are evaluating combination immune checkpoint inhibitor and tyrosine­kinase inhibitors or VEGF inhibitors for increasing overall survival in this patient population with advanced HCC.

Hepatocellular carcinoma risk in patients with HBV-related liver disease receiving antiviral therapy.

Hepatitis B virus (HBV) is a major health problem worldwide, with approximatively 240 million people living with a chronic HBV infection. HBV chronic infection remains the major cause of hepatocellular carcinoma worldwide, with more than half of HCC patients being chronic HBV carriers, even if underlying mechanisms of tumorigenesis are not totally understood. HBV-related HCC can be prevented by reducing the exposure to HBV by vaccination or by treatment of CHB infection. Current treatment of CHB are Peg-IFN alpha and oral NUCs. Treating HBV infection, either with IFN or NUCs, substantially reduces the risk of HCC development, even if antiviral therapy fails to completely eliminate HCC risk. Among treated patients, cirrhosis, HBeAg negative at baseline and failure to remain in virological remission were associated with an increased risk of HCC. The reduction of the risk of developing HCC during antiviral therapy is largely dependent upon the maintenance of virological remission, since viral load is found to be the most important factor leading to cirrhosis and its complications, including liver cancer development. The question whether Peg-IFN-alpha is superior to NUCs and whether there is a superior agent among NUCs is still controversial. Several studies demonstrated that antiviral therapy with NUCs could reduce the risk of HCC recurrence after curative treatment of HBV-related HCC.

Drug induced liver injury: from pathogenesis to liver transplantation.

Drug induced liver injury (DILI) is a necro-inflammatory liver disease caused by several drugs commonly used in clinical practice, herbs and dietary supplements prescribed for medical purposes. Despite its rarity, it represents the major cause of acute liver failure (ALF) requiring liver transplantation in USA and its frequency is increasing in Europe too. Two types of drug induced liver injury have been recognized: intrinsic and idiosyncratic. Predisposing factors may be classified in environmental, drugs- and individual- related risk factors, with the latter further distinguished in genetics and non-genetics. The liver injury can present with a hepatocellular, cholestatic or mixed pattern of disease. A definitive diagnosis of DILI is, nowadays, one of the main challenging issue in the management of these patients. Diagnosis often is based on suspicion derived from clinical history, biochemical exams and eventually on histological examination from liver biopsy. Score system may be helpful in these setting and new markers are gaining more prominence. Evaluation for liver transplantation is indicated when spontaneous resolution does not occur or in cases of ALF. Overall, the 1-year survival rate following liver transplantation is lower than that seen in patients who have been transplanted for chronic liver failure; however long-term survival is higher compared to other indications.

De novo and recurrent malignancy.

Cancer is an important cause of morbidity and mortality after liver transplantation and can occur through three mechanisms: recurrence of a recipient's pre-transplant malignancy, donor-related transmission and de novo development. Currently, the decision to list a patient with a history of malignancy is an individual one. Screening guidelines for potential donors and for recipients after transplant are still widely based on general population guidelines, while the role of chronic immunosuppression remains controversial. These shortcomings mean that patients present at diagnosis with advanced stages of the disease, often precluding curative treatments. The present review summarizes current recommendations for the screening of recipients and donors for pre- and post-transplant malignancies, and current management of recipients who develop cancer after a liver transplant.

Changes in plasma circulating microvesicles in patients with HCV-related cirrhosis after treatment with direct-acting antivirals.

BACKGROUND & AIMS: The eradication of Hepatitis C (HCV) infection by direct-acting antiviral (DAAs) agents has been linked to an amelioration of liver synthesis and regression of fibrosis. Although changes in number and type of circulating microvesicles (MVs) have been reported in cirrhosis, conclusive data on the effect of DAAs treatment on MVs profile in HCV cirrhotic patients remain scarce. METHODS: We measured the levels of endothelial, platelet and hepatocyte MVs, as well as MVs-expressing versican core protein (VCAN+) in patients with HCV-related cirrhosis at baseline, end of treatment (EOT), at 12, 24 and 48 weeks (W) after EOT by new generation flow cytometry. RESULTS: Fifty-eight patients were enrolled (86% Child's A). MVs were increased at EOT vs baseline, though only platelet MVs revealed a statistically significant difference (P < .01). MV levels did not change significantly after EOT notwithstanding a steady downward trend towards baseline levels. Conversely, VCAN + MVs dropped significantly at EOT (P < .001) and remained low throughout the follow-up. Hepatocyte MVs significantly correlated with liver stiffness (r = .40, P = .0021). Eight composite outcomes occurred during the 1-year follow-up: three portal vein thromboses (PVTs), two hepatocellular carcinomas (HCCs) and three liver decompensation. Child's B, the presence of F2 oesophageal varices (OR for interaction 19.2 [95% CI 1.45-253.7], P = .023) and platelet MVs (OR 1.026 [95% CI 1.00-1.05, P = .023) correlated significantly with clinical outcomes. CONCLUSIONS: VCAN + MVs appear to mirror the profibrotic status of the cirrhotic disease; hepatocyte MVs correlate with liver stiffness and increased platelet MV levels could be associated with a worse clinical outcome.

Survival after the diagnosis of de novo malignancy in liver transplant recipients.

In the setting of liver transplant (LT), the survival after the diagnosis of de novo malignancies (DNMs) has been poorly investigated. In this study, we assessed the impact of DNMs on survival of LT recipients as compared to corresponding LT recipients without DNM. A nested case-control study was conducted in a cohort of 2,818 LT recipients enrolled in nine Italian centres between 1985 and 2014. Cases were 244 LT recipients who developed DNMs after LT. For each case, two controls matched for gender, age, and year at transplant were selected by incidence density sampling among cohort members without DNM. The survival probabilities were estimated using the Kaplan-Meier method. Hazard ratios (HRs) of death and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models. The all-cancer 10-year survival was 43% in cases versus 70% in controls (HR = 4.66; 95% CI: 3.17-6.85). Survival was impaired in cases for all the most frequent cancer types, including lung (HR = 37.13; 95% CI: 4.98-276.74), non-Hodgkin lymphoma (HR = 6.57; 95% CI: 2.15-20.01), head and neck (HR = 4.65; 95% CI: 1.81-11.95), and colon-rectum (HR = 3.61; 95% CI: 1.08-12.07). The survival gap was observed for both early and late mortality, although the effect was more pronounced in the first year after cancer diagnosis. No significant differences in survival emerged for Kaposi's sarcoma and nonmelanoma skin cancers. The survival gap herein quantified included a broad range of malignancies following LT and prompts close monitoring during the post-transplant follow-up to ensure early cancer diagnosis and to improve survival.

Hepatitis C virus related cirrhosis decreased as indication to liver transplantation since the introduction of direct-acting antivirals: A single-center study.

AIM: To evaluate waiting list (WL) registration and liver transplantation (LT) rates in patients with hepatitis C virus (HCV)-related cirrhosis since the introduction of direct-acting antivirals (DAAs). METHODS: All adult patients with cirrhosis listed for LT at Padua University Hospital between 2006-2017 were retrospectively collected using a prospectively-updated database; patients with HCV-related cirrhosis were divided by indication for LT [dec-HCV vs HCV/ hepatocellular carcinoma (HCC)] and into two interval times (2006-2013 and 2014-2017) according to the introduction of DAAs. For each patient, indications to LT, severity of liver dysfunction and the outcome in the WL were assessed and compared between the two different time periods. For patients receiving DAA-based regimens, the achievement of viral eradication and the outcome were also evaluated. RESULTS: One thousand one hundred and ninty-four [male (M)/female (F): 925/269] patients were included. Considering the whole cohort, HCV-related cirrhosis was the main etiology at the time of WL registration (490/1194 patients, 41%). HCV-related cirrhosis significantly decreased as indication to WL registration after DAA introduction (from 43.3% in 2006-2013 to 37.2% in 2014-2017, P = 0.05), especially amongst dec-HCV (from 24.2% in 2006-2013 to 15.9% in 2014-2017, P = 0.007). Even HCV remained the most common indication to LT over time (289/666, 43.4%), there was a trend towards a decrease after DAAs introduction (from 46.3% in 2006-2013 to 39% in 2014-2017, P = 0.06). HCV patients (M/F: 43/11, mean age: 57.7 ± 8 years) who achieved viral eradication in the WL had better transplant-free survival (log-rank test P = 0.02) and delisting rate (P = 0.002) than untreated HCV patients. CONCLUSION: Introduction of DAAs significantly reduced WL registrations for HCV related cirrhosis, especially in the setting of decompensated cirrhosis.

Risk of virus and non-virus related malignancies following immunosuppression in a cohort of liver transplant recipients. Italy, 1985-2014.

This cohort study assessed, in Italy, the overall pattern of risk of de novo malignancies following liver transplantation (LT). The study group included 2,832 individuals who underwent LT between 1985 and 2014 in nine centers all over Italy. Person-years (PYs) at cancer risk were computed from 30 days after LT to the date of cancer diagnosis, to the date of death or to the end of follow-up. Excess cancer risk, as compared to the general population, was estimated using standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). During 18,642 PYs, 246 LT recipients developed 266 de novo malignancies, corresponding to a 1.8-fold higher cancer risk (95% CI: 1.6-2.0). SIRs were particularly elevated for virus-related malignancies, including Kaposi's sarcoma (SIR = 53.6, 95% CI: 30.0-88.5), non-Hodgkin lymphomas (SIR = 7.1, 95% CI: 4.8-10.1) and cervix uteri (SIR = 5.4, 95% CI: 1.1-15.8). Among virus-unrelated malignancies, elevated risks emerged for head and neck (SIR = 4.4, 95% CI: 3.1-6.2), esophagus (SIR = 6.7, 95% CI: 2.9-13.3) and adrenal gland (SIR = 22.9, 95% CI: 2.8-82.7). Borderline statistically significant elevated risks were found for lung cancer (SIR = 1.4, 95% CI: 1.0-2.1) and skin melanoma (SIR = 2.6, 95% CI: 1.0-5.3). A reduced risk emerged for prostate cancer (SIR = 0.1, 95% CI: 0.0-0.5). These findings underline the need of preventive interventions and early detection of malignancies, specifically tailored to LT recipients.

Long-term care of transplant recipients: de novo neoplasms after liver transplantation.

PURPOSE OF REVIEW: Since the first liver transplantation in the early 1960s, there have been significant improvements in the recipients' long-term outcome. Patients who have undergone transplantation are exposed to a high risk of developing neoplastic disease, not only because of their chronic immunosuppression, but also related to physiological aging, lifestyle, chronic viral infections, liver disease cause, and carcinogenic immunosuppressants. The present review covers the latest and most relevant data on de novo neoplasms after liver transplantation, and discusses their implications for clinical practice. RECENT FINDINGS: Given the impact of de novo neoplasms, in terms of morbidity and mortality, transplant teams must be prepared to diagnose and treat these conditions promptly. Dedicated cancer screening protocols are warranted. Although surveillance strategies are based on data concerning the general population, they should be customized in the light of each transplant recipient's risk factors. The resulting risk stratification is crucially important to the design of early intervention programs, and for addressing the modulation of individualized immunosuppressive regimens. SUMMARY: De novo malignancies are a significant issue for the liver transplant population, but targeted screening programs have shown that survival rates similar to those of nonimmunosuppressed patients can be achieved. New oncological surveillance strategies covering the prophylaxis, monitoring, and treatment of de novo neoplasms should take high priority in clinical research.