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Josep M Llovet

Publications and source records attributed to Josep M Llovet.

At least 19 recordsLinked to original sources
PubMed2023

International Liver Cancer Association (ILCA) white paper on hepatocellular carcinoma risk stratification and surveillance.

Major research efforts in liver cancer have been devoted to increasing the efficacy and effectiveness of surveillance for hepatocellular carcinoma (HCC). As with other cancers, surveillance programmes aim to detect tumours at an early stage, facilitate curative-intent treatment, and reduce cancer-related mortality. HCC surveillance is supported by a large randomised-controlled trial in patients with chronic HBV infection and several cohort studies in cirrhosis; however, effectiveness in clinical practice is limited by several barriers, including inadequate risk stratification, underuse of surveillance, and suboptimal accuracy of screening tests. There are several proposed strategies to address these limitations, including risk stratification algorithms and biomarkers to better identity at-risk individuals, interventions to increase surveillance, and emerging imaging- and blood-based surveillance tests with improved sensitivity and specificity for early HCC detection. Beyond clinical validation, data are needed to establish clinical utility, i.e. increased early tumour detection and reduced HCC-related mortality. If successful, these data could facilitate a precision screening paradigm in which surveillance strategies are tailored to individual HCC risk to maximise overall surveillance value. However, practical and logistical considerations must be considered when designing and implementing these validation efforts. To address these issues, ILCA (the International Liver Cancer Association) adjourned a single topic workshop on HCC risk stratification and surveillance in June 2022. Herein, we present a white paper on these topics, including the status of the field, ongoing research efforts, and barriers to the translation of emerging strategies.

Humans↗
PubMed2006

Downregulation of KLF6 is an early event in hepatocarcinogenesis, and stimulates proliferation while reducing differentiation.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) has the most rapidly rising cancer incidence in the US and Europe. The KLF6 tumor suppressor is frequently inactivated in HCC by loss-of-heterozygosity (LOH) and/or mutation. METHODS: Here we have analyzed 33 HBV- and 40 HCV-related HCCs for mRNA expression of wildtype KLF6 (wtKLF6) as well as the KLF6 variant 1 (SV1), a truncated, growth-promoting variant that antagonizes wtKLF6 function. The HCV-related tumors analyzed represented the full histologic spectrum from cirrhosis and dysplasia to metastatic cancer. RESULTS: Expression of KLF6 mRNA is decreased in 73% of HBV-associated HCCs compared to matched surrounding tissue (ST), with reductions of approximately 80% in one-third of the patients. KLF6 mRNA expression is also reduced in dysplastic nodules from patients with HCV compared to cirrhotic livers (p<0.005), with an additional, marked decrease in the very advanced, metastatic stage (p<0.05). An increased ratio of KLF6SV1/wt KLF6 is present in a subset (6/33, 18%) of the HBV-related HCCs compared to matched ST. Reconstituting KLF6 in HepG2 cells by retroviral infection decreased proliferation and related markers including cyclin D1 and beta-catenin, increased cellular differentiation based on induction of albumin, E-cadherin, and decreased alpha fetoprotein. CONCLUSIONS: We conclude that reduced KLF6 expression is common in both HBV- and HCV-related HCCs and occurs at critical stages during cancer progression. Effects of KLF6 are attributable to regulation of genes controlling hepatocyte growth and differentiation.

Biomarkers↗
PubMed2006

A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis.

BACKGROUND & AIMS: Small liver nodules approximately 2 cm are difficult to characterize by radiologic or pathologic examination. Our aim was to identify a molecular signature to diagnose early hepatocellular carcinoma (HCC). METHODS: The transcriptional profiles of 55 candidate genes were assessed by quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) in 17 dysplastic nodules (diameter, 10 mm) and 20 early HCC (diameter, 18 mm) from HCV cirrhotic patients undergoing resection/transplantation and 10 nontumoral cirrhotic tissues and 10 normal liver tissues. Candidate genes were confirmed by quantitative RT-PCR in 20 advanced HCCs and by immunohistochemistry in 75 samples and validated in an independent set of 29 samples (dysplastic nodules [10] and small HCC [19; diameter, 20 mm]). RESULTS: Twelve genes were significantly, differentially expressed in early HCCs compared with dysplastic nodules (>2-fold change; area under the receiver operating characteristic curve > or =0.8): this included TERT, GPC3, gankyrin, survivin, TOP2A, LYVE1, E-cadherin, IGFBP3, PDGFRA, TGFA, cyclin D1, and HGF. Logistic regression analysis identified a 3-gene set including GPC3 (18-fold increase in HCC, P = .01), LYVE1 (12-fold decrease in HCC, P = .0001), and survivin (2.2-fold increase in HCC, P = .02), which had a discriminative accuracy of 94%. The validity of the gene signature was confirmed in a prospective testing set. GPC3 immunostaining was positive in all HCCs and negative in dysplastic nodules (22/22 vs 0/14, respectively, P < .001). Nuclear staining for survivin was positive in 12 of 13 advanced HCC cases and in 1 of 9 early tumors. CONCLUSIONS: Molecular data based on gene transcriptional profiles of a 3-gene set allow a reliable diagnosis of early HCC. Immunostaining of GPC3 confirms the diagnosis of HCC.

Biomarkers, Tumor↗
PubMed2006

Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis.

Tumor recurrence after resection of hepatocellular carcinoma (HCC) can occur early (<2 years) or late (>2 years) as metastases or de novo tumors. Interferon (IFN) has the potential for chemoprevention against hepatitis C virus (HCV)-related cirrhosis. A predetermined group of 150 HCV RNA-positive patients undergoing resection of early- to intermediate-stage HCC was stratified into 80 HCV-pure (hepatitis B anticore antibody [anti-HBc]-negative) and 70 mixed HCV+hepatitis B virus (HBV) (anti-HBc-positive) groups, then randomized to IFN-alpha (3 million units 3 times every week for 48 weeks [n = 76]) versus control (n = 74). The primary end point was recurrence-free survival (RFS); secondary end points were disease-specific and overall survival. Intention-to-treat and subgroup analysis on adherent patients were conducted. Treatment effects on early/late recurrences were assessed using multiple Cox regression analysis. No patient experienced life-threatening adverse events. There were 28 adherent patients (37%). After 45 months of median follow-up, overall survival was 58.5%, and no significant difference in RFS was detectable between the two study arms (24.3% vs. 5.8%; P = .49). HCC recurred in 100 patients (48 IFN-treated, 52 controls), with a 50% reduction in late recurrence rate in the treatment arm. HCC multiplicity and vascular invasion were significantly related to recurrence (P = .01 and .0003). After viral status stratification, while no treatment effect was apparent in the mixed HCV+HBV population and on early recurrences (72 events), there was a significant benefit on late recurrences (28 events) in HCV-pure patients adherent to treatment (HR: 0.3; 95% CI: 0.09-0.9; P = .04). In conclusion, IFN does not affect overall prevention of HCC recurrence after resection, but it may reduce late recurrence in HCV-pure patients receiving effective treatment.

Adult↗
PubMed2006

Expanded criteria for hepatocellular carcinoma through down-staging prior to liver transplantation: not yet there.

The accepted treatment strategy for hepatocellular carcinoma (HCC) is supported by randomized controlled trials (RCTs), meta-analysis, and large cohort studies. For instance, the Milan criteria applied for indicating liver transplantation have been validated by several cohort studies including more than 1000 patients. Regarding medical treatments, approximately 80 RCTs have been published so far in HCC. These studies provide the evidence to support chemoembolization as the treatment for patients at intermediate stage (meta-analysis of 6 RCTs) and show the lack of benefit of tamoxifen assessed in 12 RCTs including more than 1500 patients. In this scenario, what is the evidence to advocate for the expansion of HCC criteria through down-staging prior to liver transplantation? Such an approach has never been tested through RCTs or even well-designed cohort studies including enough patients and adequate follow-up. Only a few small studies with heterogeneous target populations and treatments applied are available. The results of these studies are inconsistent and do not provide compelling evidence to accept down-staging as a standard of care.

Carcinoma, Hepatocellular↗
PubMed2006

Molecular diagnosis of chronic liver disease and hepatocellular carcinoma: the potential of gene expression profiling.

Gene expression profile analysis through DNA microarrays and other high-throughput technologies permit simultaneous investigation of all genes within a biologic sample, providing a snapshot of the transcriptional state of healthy or diseased tissue. Although most of the current applications are still geared toward research (study of disease mechanisms/signaling pathways involved, identification of novel oncogenes/tumor suppressor genes), clinical diagnostic applications of this approach are beginning to enter more routine molecular usage. There are clear examples where a group of genes, or "signature," can provide clinically useful information (e.g., cancer prognosis and response to treatment). Importantly, the identification of genes that are up-regulated during tumorigenesis is heralding a new era of targeted molecular therapies in oncology. In addition, the high capacity of the technologies available allow for the identification of new biomarkers for early diagnosis. In the future, gene expression profiling ("disease fingerprinting") is likely to complement liver biopsy in the molecular differential diagnosis of chronic liver diseases and hepatocellular carcinoma (HCC). There has already been some success in the identification of subtypes of HCC based on derived sets of signature gene clusters. Data recently reported have been able to provide the first molecular classification of HCC, although more comprehensive studies are required to confirm these results and translate them into the clinical practice. In fact, variations in gene expression in normal and diseased livers, as well technical factors, are obstacles to the routine use of microarray-based methods in the liver clinic. Continued progress is anticipated in the practical application of gene array methods to refine diagnosis and therapy of HCC.

Carcinoma, Hepatocellular↗
PubMed2005

Applicability of adult-to-adult living donor liver transplantation.

BACKGROUND/AIMS: The applicability of adult-to-adult living donor liver transplantation has not been established yet. We report the first data in a European center of the process leading to this procedure from the first moment the patients were informed about it. METHODS: In phase 1 of the process, 121 adult patients enlisted for cadaveric liver transplantation and their relatives were informed of the technical aspects, advantages and risks of living donor liver transplantation, and the essential criteria for living donation. In phase 2, potential donors identified in phase 1 were evaluated in depth. RESULTS: Twenty-one (17%) patients underwent living donor liver transplantation. This procedure was not performed in 60 patients (50%) for reasons concerning the patients themselves, especially their refusal to receive living donor liver transplantation from a relative (30%). Forty patients (33%) did not undergo living donor liver transplantation for reasons concerning potential donors: donors were not identified (14%), declined the donation (13%), or were refused for technical reasons (6%). The expected waiting time to transplantation was longer in patients who underwent living donor liver transplantation than in those who did not. CONCLUSIONS: The applicability of adult-to-adult living donor liver transplantation is low, mainly because of reasons related to potential recipients.

Adult↗
PubMed2005

Updated treatment approach to hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and its incidence will further increase, to reach a plateau in 2015-2020. The natural history of the disease is quite well known, except for its early stages, because the majority of patients at this stage are treated with radical approaches. Staging systems are key to predict the prognostics of patients with cancer, to stratify the patients according to prognostic variables in the setting of clinical trials, and to guide the therapeutic approach. The current knowledge of the disease, however, is not sufficient for recommending a staging system to be used worldwide. The conventional staging systems-Okuda stage, and TNM stage-have shown important limitations for classifying patients. Several new systems have been recently proposed, but only three of them have been validated. The Barcelona Clinic Liver Cancer (BCLC) staging classification links the stage of the disease to a specific treatment strategy. The Japan Integrated Staging (JIS) score has been proposed and used in Japan, although it needs Western validation. The Cancer of the Liver Italian Program (CLIP) score is mainly proposed for patients with advanced tumors. Early detection of HCC through surveillance programs allows the application of potentially curative therapies, such as resection, liver transplantation, and percutaneous ablation in patients with early tumors. The applicability of these treatments varies according to geographical distribution: from 50% to 70% of cases in Japan; 25% to 40% of cases in Europe and the United States; and fewer than 10% in Africa. There are no randomized controlled trials (RCTs) comparing any of the three major therapies. These studies are not feasible in the West. Therefore, there is no firm evidence to establish the optimal first-line treatment for small single HCC in patients with well-preserved liver function. Resection and transplantation achieve the best outcomes in well-selected candidates (5-year survival of 60%-70%), and compete as the first option from an intention-to-treat perspective. If surgery is precluded, local, nonsurgical therapies are applied. Percutaneous treatments provide good results (5-year survival of 40%-50%), but are unable to achieve response rates and outcomes comparable to those for surgical treatments, even when applied as the first option. Radiofrequency thermal ablation provides slightly better objective response rates than ethanol injection, but no survival advantages have been fully demonstrated. The remaining treatments have been assessed in the setting of around 70 RCTs conducted during the past 25 years. Chemoembolization has been shown to provide modest survival advantages in two RCTs and a metaanalysis, and is currently the mainstay of treatment in 10% of the whole HCC population. The ideal candidates for this option are patients with well-preserved liver function (Child-Pugh class A) and multinodular asymptomatic tumors without vascular invasion. Further RCTs are needed to assess the best chemotherapeutic agent and the ideal re-treatment schedule. There is no firstline option for patients with advanced HCC (vascular invasion, extrahepatic spread, or cancer-related symptoms). Systemic doxorubicin provides partial responses in 10% of cases, without proven survival advantages, and well-known treatment-related complications. Several other treatments, such as immunotherapy, internal radiation, tamoxifen, or anti-androgen agents, have not shown any relevant anti-tumoral effect or survival benefit. New drugs, such as tyrosine kinase inhibitors and anti-angiogenic agents, are currently being tested in the setting of clinical trials.

Carcinoma, Hepatocellular↗
PubMed2005

Liver transplantation for hepatocellular carcinoma: is expansion of criteria justified?

Hepatocellular carcinoma (HCC) is a major health problem worldwide, involving more than a half million new cases yearly, with an age-adjusted incidence of 5.5 to 14.9 per 10(5) population. In some areas of Asia and the Middle East, HCC ranks as the first cause of death due to cancer. The incidence of HCC is increasing in Europe and the United States, and it is currently the leading cause of death among cirrhotic patients. It is estimated that by the year 2010, the number of patients with HCC awaiting liver transplant in the United States will outnumber the supply of cadaver organs.

Cadaver↗
PubMed2005

Resection and liver transplantation for hepatocellular carcinoma.

Surveillance programs in cirrhotic patients enable the detection of hepatocellular carcinoma (HCC) at early stages, when the tumor is amenable to curative treatments (60% of cases in Japan; 25 to 40% in Europe and the United States). Resection is the mainstay of treatment in noncirrhotic patients and in cirrhotics with well-preserved liver function. In modern series, a perioperative mortality < or = 3% and 5-year survival rates above 50% are expected. Tumor recurrence complicates half of the cases at 3 years, but there is no unquestionable preventive treatment. Liver transplantation provides excellent outcomes applying the Milan criteria (single nodule < or = 5 cm or two or three nodules < or = 3 cm), with 5-year survival rates of 70% and low recurrence rates. Although expansion of selection criteria is appealing, it should be assessed in the setting of prospective well-designed studies. Intention-to-treat analysis has shown that wide extended indications lead to 25% 5-year survival rates. Living donor liver transplantation is having a minor impact in HCC management. Molecular markers are needed to better select the candidates for surgery.

Carcinoma, Hepatocellular↗
PubMed2005

Non-surgical therapies of hepatocellular carcinoma.

Early detection of hepatocellular carcinoma (HCC) through surveillance programmes allows potentially curative therapies such as resection, liver transplantation and percutaneous ablation to be applied in 40% of the patients. In non-surgical candidates, percutaneous treatments are the best therapeutic approach, and may improve survival in patients with well preserved liver function and small tumours that achieve initial complete response. Applying these criteria 5-year survival rates above 50% are achieved. Radio frequency thermal ablation provides slightly better objective response rates than ethanol injection, but no survival advantages have been reported. At more advanced stages, only chemoembolization has been shown to improve survival in well-selected candidates.

Carcinoma, Hepatocellular↗
PubMed2005

Liver transplantation in hepatocellular carcinoma.

Liver transplantation is one option of surgical treatment for cirrhotic patients with hepatocellular carcinoma, it not only treats the malignancy but also the underlying disease. After an initial period of disappointing results, mainly due to lack of adequate selection, survival nowadays is similar to that obtained by cirrhotic patients without tumor. Currently the scarcity of donors is the main limitation in the treatment of this type of patients. Increased time on the waiting list does compromise the results if they are analyzed in an intention-to-treat basis. Adjuvant therapy on the waiting list (ethanol injection, chemoembolization, surgery, etc.) or the use of marginal grafts in order to increase the donor pool may be some alternatives to overcome this deficit. The development of adult living donor liver transplantation has proved to be a good alternative in this type of patients even if they do not fulfill the conventional criteria.

Carcinoma, Hepatocellular↗
PubMed2004

Hepatitis C recurrence is more severe after living donor compared to cadaveric liver transplantation.

Preliminary reports suggested that hepatitis C virus (HCV) infection has a more aggressive course following living donor liver transplantation (LDLT) compared to cadaveric liver transplantation (CLT). The aim of this prospective study was to establish if HCV disease recurrence differs between LDLT and CLT. A cohort of 116 consecutive HCV-infected patients undergoing 117 LTs in a single center from March 2000 to August 2003 were followed-up, including systematic liver biopsies. Severe recurrence (SR) was defined as biopsy-proven cirrhosis and/or the occurrence of clinical decompensation. After a median follow-up of 22 months (2.6-44 months), 26 (22%) patients developed SR (decompensation in 12), involving 17 (18%) of 95 patients undergoing CLT and 9 (41%) of 22 undergoing LDLT. The 2-year probability of presenting SR was significantly higher in LDLT compared to CLT (45% vs. 22%, P = .019). By univariate analysis LDLT (P = .019) and an ALT higher than 80 IU/L 3 months after LT (P = .022) were predictors of SR. In 93 patients from whom a liver biopsy was available 3 months after LT, a lobular necroinflammatory score >1 (P < .01), LDLT (P < .01), and biliary complications (P = .046) were associated with SR. However, the only variables independently associated with SR were LDLT (odds ratio [OR], = 2.8; 95% CI,1.19-6.6; P = .024) and a lobular necroinflammatory score > 1 (OR, 3.1; 95% CI, 1.2-8; P = .013). In conclusion, HCV recurrence is more severe in LDLT compared to CLT. Although our results were based on a single-center experience, they should be considered in the decision-making process of transplant programs, since severe HCV recurrence may ultimately compromise graft and patient survival.

Adult↗