- Padova, Veneto, Italy
Alessandro Vitale
Università degli Studi di Padova, DISCOG, Faculty Member
Tumor progression before orthotopic liver transplantation (OLT) is the main cause of dropouts from waiting lists among patients with hepatocellular carcinoma (HCC). Performing a porto-caval shunt (PCS) before parenchymal liver transection... more
Tumor progression before orthotopic liver transplantation (OLT) is the main cause of dropouts from waiting lists among patients with hepatocellular carcinoma (HCC). Performing a porto-caval shunt (PCS) before parenchymal liver transection has the potential to allow an extended hepatectomy in patients with decompensated liver cirrhosis, reducing portal hyperflow and therefore the sinusoidal shear-stress on the remnant liver. We report the case of a 59-year-old man affected by hepatitis C virus (HCV)-related decompensated liver cirrhosis (Child Pugh score presentation, C-10; Model for End Stage Liver Disease score, 18) and HCC (2 lesions of 2 and 2.8 cm). The patient began the evaluation to join the OLT waiting list, but, in the 3 months required to complete the evaluation, he developed tumor progression: 3 HCC lesions, the largest 1 with a diameter of about 4.4 cm. These findings excluded transplantation criteria and the patient was referred to our center. After appropriate preoperat...
Research Interests: Medicine, Hepatitis C, Case Report, Humans, Liver Cirrhosis, and 15 moreAlcoholism, Female, Male, Hepatocellular Carcinoma, Hepatitis C Virus, Liver Transplantation, Middle Aged, Adult, Liver Resection, Cirrhosis, Orthotopic Liver Transplantation, Immunosuppressive Agents, Hepatectomy, Liver neoplasms, and Medical and Health Sciences
As observed by Jeon and Ranjan, 1 suboptimal donor livers are an essential resource for liver transplantation (LT) candidates. In our prospective randomized study, 2 the harvesting technique showed a relevant prognostic impact on post-LT... more
As observed by Jeon and Ranjan, 1 suboptimal donor livers are an essential resource for liver transplantation (LT) candidates. In our prospective randomized study, 2 the harvesting technique showed a relevant prognostic impact on post-LT outcome when suboptimal ...
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Liver transplantation (LT) represents the only chance of long-term survival for patients with end-stage liver disease. When the mortality rate for transplant patients returns to the same level as that for the general population, they can... more
Liver transplantation (LT) represents the only chance of long-term survival for patients with end-stage liver disease. When the mortality rate for transplant patients returns to the same level as that for the general population, they can be considered statistically cured. However, cure models in the setting of LT have never been applied. Data from 1371 adult patients undergoing LT for the first time between January 1999 and December 2012 at 2 Italian centers were reviewed in order to establish probabilities of being cured by LT. A parametric Weibull model was applied to compare the mortality rate after LT to the rate expected for the general population (matched by sex and age). The observed 3-, 5-, and 10-year overall survival rates after LT were 77.8%, 73.3%, and 65.6%, respectively, and they did not differ between the 2 centers (P = 0.37). The cure fraction for the entire study population was 63.4% (95% confidence interval = 52.6%-72.0%), and the time to cure was 10 years with a 90% confidence level. The best cure fraction was observed for younger recipients without hepatitis C virus (HCV) who had favorable donor-recipient matches, that is, low Donor Model for End-Stage Liver Disease (D-MELD) scores (90.1%); conversely, the lowest probability was observed for elderly HCV recipients with high D-MELD scores (34.6%). The time to cure was 6.22 years for non-HCV patients and 14.78 years for HCV patients. The median survival time for uncured patients was 2.29 years. Among uncured recipients, the longest survival time was observed for younger patients (7.31 years). In conclusion, we provide here a new clinical measure for LT suggesting that survival after transplantation can approximate that of the general population and provide a statistical cure.
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Partial hepatectomy (PH) and liver transplantation (LT) compete as first-line treatment for hepatocellular carcinoma (HCC). A prospectively collected database was retrospectively reviewed to establish when PH can compete with LT. Between... more
Partial hepatectomy (PH) and liver transplantation (LT) compete as first-line treatment for hepatocellular carcinoma (HCC). A prospectively collected database was retrospectively reviewed to establish when PH can compete with LT. Between 1991 and 2002, PH was performed in 131 cases of HCC (Child-Pugh A-B, technically resectable tumor without metastases). To ascertain patient survival after PH, we compared this series with a group of 40 HCC patients (G1-G2 HCC with no gross vascular invasion or metastasis) enlisted for liver transplantation during the same period. The 1-, 3-, and 5-year intention-to-treat survival rates were 75%, 52%, and 31% for resection and 89%, 71%, and 63% for transplantation. Two tumor-related variables (gross vascular invasion and histological grade) and three liver function parameters (Child-Pugh score, bilirubin, Okuda stage) proved to be independent predictors of survival after resection, whereas nodule size and number, and Milan criteria did not. The 5-year survival of the best candidates for resection (favorable tumor biology with very well preserved liver function, n = 52) was 58%. On a descriptive basis alone, this result did not differ significantly from the outcome in LT patients. PH patients with a poorly differentiated tumor and/or gross vascular invasion (n = 28) had the worst outcome, irrespective of their liver function parameters. For technically resectable tumors without aggressive features (G3 or macroscopic vascular invasion), PH can only compete with LT, in terms of long-term survival, when patients with a well-preserved liver function are selected.
Research Interests: Gastroenterology, Medicine, Multivariate Analysis, Italy, Humans, and 15 moreInternal Medicine, Female, Male, Hepatocellular Carcinoma, Liver Transplantation, Liver Function, Bilirubin, Middle Aged, Retrospective Studies, Prognosis, Partial Hepatectomy, Surgical, Patient selection, Hepatectomy, and Liver neoplasms
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Primary transplantation offers longer life-expectancy in comparison to hepatic resection (HR) for hepatocellular carcinoma (HCC) followed by salvage transplantation; however, livers not used for primary transplantation can be reallocated... more
Primary transplantation offers longer life-expectancy in comparison to hepatic resection (HR) for hepatocellular carcinoma (HCC) followed by salvage transplantation; however, livers not used for primary transplantation can be reallocated to the remaining waiting-list patients, thus, the harm caused to resected patients could be balanced, or outweighed, by the benefit obtained from reallocation of livers originating from HCC patients first being resected. A Markov model was developed to investigate this issue based on literature data or estimated from the United Network for Organ Sharing database. Markov model shows that primary transplantation offers longer life-expectancy in comparison to HR and salvage transplantation if 5-year posttransplant survival remains higher than 60%. The balance between the harm for resected patients and the benefit for the remaining waiting list depends on (a) the proportion of HCC candidates, (b) the percentage shifted to HR and (c) the median expected time-to-transplant. Faced with a low proportion of HCC candidates, the harm caused to resected patients was higher than the benefit that could be obtained for the waiting-list population from re-allocation of extra livers. An increased proportion of HCC candidates and/or an increased median time-to-transplant could lead to a benefit for waiting-list patients that outweighs this harm.
Research Interests: Treatment Outcome, Organ Donation and Transplantation, Medicine, Transplantation, Humans, and 14 moreMarkov chains, Hepatocellular Carcinoma, Liver Transplantation, Life Expectancy, Fibrosis, Aged, Middle Aged, Harm, Time Factors, Liver Resection, Statistical models, Hepatectomy, Liver neoplasms, and Medical and Health Sciences
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Worldwide, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) significantly increases mortality and morbidity. The Coronavirus Disease 2019 (COVID-19) outbreak has had a considerable impact on healthcare systems all around... more
Worldwide, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) significantly increases mortality and morbidity. The Coronavirus Disease 2019 (COVID-19) outbreak has had a considerable impact on healthcare systems all around the world, having a significant effect on planned patient activity and established care pathways, in order to meet the difficult task of the global pandemic. Patients with hepatocellular carcinoma (HCC) are considered a particularly susceptible population and conceivably at increased risk for severe COVID-19 because of two combined risk factors: chronic advanced liver disease and HCC itself. In these challenging times, it is mandatory to reshape clinical practice in a prompt way to preserve the highest standards of patient care and safety. However, due to the stay-at-home measures instituted to stop the spread of COVID-19, HCC surveillance has incurred a dramatic drop, and care for HCC patients has been rearranged by refining the algorithm for HCC tr...
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Background: MicroRNAs (miRNAs) have been proposed as biomarkers in hepatocellular carcinoma (HCC). We aim at evaluating miR-21 and miR-122 in HCC patients treated with drug-eluting beads transarterial chemoembolization (DEB-TACE) as... more
Background: MicroRNAs (miRNAs) have been proposed as biomarkers in hepatocellular carcinoma (HCC). We aim at evaluating miR-21 and miR-122 in HCC patients treated with drug-eluting beads transarterial chemoembolization (DEB-TACE) as prognostic biomarkers and investigating their correlation with hypoxia inducible factor-1α (HIF-1α) serum levels. Methods: In this retrospective study, 12 healthy subjects, 28 cirrhotics, and 54 HCC patients (tested before and four weeks after DEB-TACE) were included. Whole blood miR-21 and miR-122 levels were measured by quantitative real time (qRT)-PCR, while serum HIF-1α was assessed by an enzyme-linked immunosorbent assay (ELISA) test. Results: The highest level of miR-21 was found in cirrhotics, while HCC patients had the highest level of miR-122 (which was even higher in “viral” HCC, p = 0.006). miR-21 ratio (after/before DEB-TACE) and miR-122 below their respective cut-offs identified patients with longer progression-free survival (p = 0.0002 and ...
Research Interests: Medicine and biomedicines
Simple Summary The XXL trial has recently shown that biological downstaging is an effective strategy to also allow liver transplantation into patients with more advanced hepatocellular carcinoma without alternative curative options. Some... more
Simple Summary The XXL trial has recently shown that biological downstaging is an effective strategy to also allow liver transplantation into patients with more advanced hepatocellular carcinoma without alternative curative options. Some potential limits of the XXL downstaging protocol are (a) the rather high downstaging failure rate (i.e., 32%), and (b) the additional prioritization of transplantation for patients with a potential good prognosis without transplant, i.e., those obtaining a complete response to downstaging. In this study, we showed that, using aggressive surgical downstaging, it is possible to considerably decrease the downstaging failure rate. Moreover, we showed that it is possible to avoid an immediate prioritization of transplantation for patients with a sustained complete response to downstaging by applying a “wait and see” policy. This policy seems to spare a relevant number of organs without worsening patient outcome. Abstract The XXL trial represents the firs...
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Purpose: We aimed at assessing the impact of surveillance on long-term survival in HCC patients. Methods: From the ITA.LI.CA database, we selected 1028 cases with long (≥5 years, LS group) and 2721 controls with short-term survival (<5... more
Purpose: We aimed at assessing the impact of surveillance on long-term survival in HCC patients. Methods: From the ITA.LI.CA database, we selected 1028 cases with long (≥5 years, LS group) and 2721 controls with short-term survival (<5 years, SS group). The association between surveillance and LS was adjusted for confounders by multivariable logistic regression analysis. Survival of surveilled patients was presented both as observed and corrected for the lead-time bias, and the comparison of survival between surveillance and no surveillance groups was also performed after balancing the baseline characteristics with inverse probability weights (IPW). Results: LS patients were more frequently diagnosed under surveillance (p < 0.0001), and had more favorable baseline characteristics. Surveillance was an independent predictor of LS (OR = 1.413, 95% CI 1.195–1.671; p < 0.0001). The observed and the lead-time corrected survival of surveilled patients were significantly longer com...
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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... more
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 ag...
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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Diagnostic, prognostic, and predictive biomarkers are urgently needed in order to improve patient survival. Indeed, the most widely used... more
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Diagnostic, prognostic, and predictive biomarkers are urgently needed in order to improve patient survival. Indeed, the most widely used biomarkers, such as alpha-fetoprotein (AFP), have limited accuracy as both diagnostic and prognostic tests. Liver biopsy provides an insight on the biology of the tumor, but it is an invasive procedure, not routinely used, and not representative of the whole neoplasia due to the demonstrated intra-tumoral heterogeneity. In recent years, liquid biopsy, defined as the molecular analysis of cancer by-products, released by the tumor in the bloodstream, emerged as an appealing source of new biomarkers. Several studies focused on evaluating extracellular vesicles, circulating tumor cells, cell-free DNA and non-coding RNA as novel reliable biomarkers. In this review, we aimed to provide a comprehensive overview on the most relevant available evidence on novel ci...
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Prognostic assessment in patients with HCC remains an extremely difficult clinical task due to the complexity of this cancer where tumour characteristics interact with degree of liver dysfunction, patient general health status, and a... more
Prognostic assessment in patients with HCC remains an extremely difficult clinical task due to the complexity of this cancer where tumour characteristics interact with degree of liver dysfunction, patient general health status, and a large span of available treatment options. Several prognostic systems have been proposed in the last three decades, both from the Asian and European/North American countries. Prognostic scores, such as the CLIP score and the recent MESH score, have been generated on a solid statistical basis from real life population data, while staging systems, such as the BCLC scheme and the recent CNLC classification, have been created by experts according to recent HCC prognostic evidences from the literature. A third category includes combined prognostic systems that can be used both as prognostic scores and staging systems. A recent example is the ITA.LI.CA prognostic system including either a prognostic score and a simplified staging system. This review focuses f...
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The COVID-19 pandemic caused temporary drops in the supply of organs for transplantation, leading to renewed debate about whether T2 hepatocellular carcinoma (HCC) patients should receive priority during these times. The aim of this study... more
The COVID-19 pandemic caused temporary drops in the supply of organs for transplantation, leading to renewed debate about whether T2 hepatocellular carcinoma (HCC) patients should receive priority during these times. The aim of this study was to provide a quantitative model to aid decision-making in liver transplantation for T2 HCC. We proposed a novel ethical framework where the individual transplant benefit for a T2 HCC patient should outweigh the harm to others on the waiting list, determining a “net benefit”, to define appropriate organ allocation. This ethical framework was then translated into a quantitative Markov model including Italian averages for waiting list characteristics, donor resources, mortality, and transplant rates obtained from a national prospective database (n = 8567 patients). The net benefit of transplantation in a T2 HCC patient in a usual situation varied from 0 life months with a model for end-stage liver disease (MELD) score of 15, to 34 life months with...
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Since the introduction of Milan Criteria, all scoring models describing the prognosis of hepatocellular cancer (HCC) after liver transplantation (LT) have been exclusively based on characteristics available at surgery, therefore... more
Since the introduction of Milan Criteria, all scoring models describing the prognosis of hepatocellular cancer (HCC) after liver transplantation (LT) have been exclusively based on characteristics available at surgery, therefore neglecting the intention-to-treat principles. This study aimed at developing an intention-to-treat model through a competing-risk analysis. Using data available at first referral, an upper limit of tumor burden for downstaging was identified beyond which successful LT becomes an unrealistic goal. Twelve centers in Europe, United States, and Asia (Brussels, Sapienza Rome, Padua, Columbia University New York, Innsbruck, Medanta-The Medicity Dehli, Hong Kong, Kyoto, Kaohsiung Taiwan, Mainz, Fukuoka, Shulan Hospital Hangzhou) created a Derivation (n = 2318) and a Validation Set (n = 773) of HCC patients listed for LT between January 2000–March 2017. In the Derivation Set, the competing-risk analysis identified two independent covariables predicting post-transpla...
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Despite progress in our understanding of the biology of hepatocellular carcinoma (HCC), this tumour remains difficult-to-cure for several reasons, starting from the particular disease environment where it arises—advanced chronic liver... more
Despite progress in our understanding of the biology of hepatocellular carcinoma (HCC), this tumour remains difficult-to-cure for several reasons, starting from the particular disease environment where it arises—advanced chronic liver disease—to its heterogeneous clinical and biological behaviour. The advent, and good results, of immunotherapy for cancer called for the evaluation of its potential application also in HCC, where there is evidence of intra-hepatic immune response activation. Several studies advanced our knowledge of immune checkpoints expression in HCC, thus suggesting that immune checkpoint blockade may have a strong rationale even in the treatment of HCC. According to this background, initial studies with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, and nivolumab, a programmed cell death protein 1 (PD-1) antibody, showed promising results, and further studies exploring the effects of other immune checkpoint inhibitors, alone or with...
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Growing interest is recently being focused on the role played by the platelets in favoring hepatocellular cancer (HCC) growth and dissemination. The present review reports in detail both the experimental and clinical evidence published on... more
Growing interest is recently being focused on the role played by the platelets in favoring hepatocellular cancer (HCC) growth and dissemination. The present review reports in detail both the experimental and clinical evidence published on this topic. Several growth factors and angiogenic molecules specifically secreted by platelets are directly connected with tumor progression and neo-angiogenesis. Among them, we can list the platelet-derived growth factor, the vascular endothelial growth factor, the endothelial growth factor, and serotonin. Platelets are also involved in tumor spread, favoring endothelium permeabilization and tumor cells’ extravasation and survival in the bloodstream. From the bench to the clinics, all of these aspects were also investigated in clinical series, showing an evident correlation between platelet count and size of HCC, tumor biological behavior, metastatic spread, and overall survival rates. Moreover, a better understanding of the mechanisms involved in...
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Prognostic assessment in patients with hepatocellular carcinoma (HCC) remains controversial. Using the Italian Liver Cancer (ITA.LI.CA) database as a training set, we sought to develop and validate a new prognostic system for patients... more
Prognostic assessment in patients with hepatocellular carcinoma (HCC) remains controversial. Using the Italian Liver Cancer (ITA.LI.CA) database as a training set, we sought to develop and validate a new prognostic system for patients with HCC. Prospective collected databases from Italy (training cohort, n = 3,628; internal validation cohort, n = 1,555) and Taiwan (external validation cohort, n = 2,651) were used to develop the ITA.LI.CA prognostic system. We first defined ITA.LI.CA stages (0, A, B1, B2, B3, C) using only tumor characteristics (largest tumor diameter, number of nodules, intra- and extrahepatic macroscopic vascular invasion, extrahepatic metastases). A parametric multivariable survival model was then used to calculate the relative prognostic value of ITA.LI.CA tumor stage, Eastern Cooperative Oncology Group (ECOG) performance status, Child-Pugh score (CPS), and alpha-fetoprotein (AFP) in predicting individual survival. Based on the model results, an ITA.LI.CA integra...