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15 pages, 1100 KiB

Open AccessArticle

A Nomogram-Based Prognostic Model for Advanced Hepatocellular Carcinoma Patients Treated with Sorafenib: A Multicenter Study

by Giovanni Marasco, Francesco Poggioli, Antonio Colecchia, Giuseppe Cabibbo, Filippo Pelizzaro, Edoardo Giovanni Giannini, Sara Marinelli, Gian Ludovico Rapaccini, Eugenio Caturelli, Mariella Di Marco, Elisabetta Biasini, Fabio Marra, Filomena Morisco, Francesco Giuseppe Foschi, Marco Zoli, Antonio Gasbarrini, Gianluca Svegliati Baroni, Alberto Masotto, Rodolfo Sacco, Giovanni Raimondo, Francesco Azzaroli, Andrea Mega, Gianpaolo Vidili, Maurizia Rossana Brunetto, Gerardo Nardone, Luigina Vanessa Alemanni, Elton Dajti, Federico Ravaioli, Davide Festi, Franco Trevisani and on behalf of the Italian Liver Cancer (ITA.LI.CA.) Group Show full author list Hide full author list

Cancers 2021, 13(11), 2677; https://doi.org/10.3390/cancers13112677 - 29 May 2021

Cited by 9 | Viewed by 3090

Abstract

Among scores and staging systems used for HCC, none showed a good prognostic ability in patients with advanced HCC treated with Sorafenib. We aimed to evaluate predictive factors of overall survival (OS) and drug response in HCC patients undergoing Sorafenib included in the [...] Read more.

Among scores and staging systems used for HCC, none showed a good prognostic ability in patients with advanced HCC treated with Sorafenib. We aimed to evaluate predictive factors of overall survival (OS) and drug response in HCC patients undergoing Sorafenib included in the Italian Liver Cancer (ITA.LI.CA.) multicenter cohort. Patients in the ITA.LI.CA database treated with Sorafenib and updated on 30 June 2019 were included. Demographic and clinical data before starting Sorafenib treatment were considered. For the evaluation of predictive factors for OS, a time-dependent Cox proportional hazard model was used. A total of 1107 patients were included in our analysis. The mean age was 64.3 years and 81.7% were male. Most patients were staged as BCLC B (205, 18.9%) or C (706, 65.1%). The median time of Sorafenib administration was 4 months (interquartile range (IQR) 2–12), and the median OS was 10 months (IQR: 4–20). A total of 263 patients (33.8%) out of 780 with available evaluation experienced objective tumoral response to Sorafenib. The Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (hazard ratio (HR) 1.284), maximum tumoral diameter (HR 1.100), plasma total bilirubin (HR 1.119), aspartate amino transferase assessed as multiple of the upper normal value (HR 1.032), alpha-fetoprotein ≥200 ng/mL (HR 1.342), hemoglobin (HR 0.903) and platelet count (HR 1.002) were associated with OS at multivariate Cox regression analysis. Drug response was predicted by maximum tumoral diameter and platelet count. A novel prognostic nomogram for patients undergoing Sorafenib is hereby proposed. The novelty introduced is the comprehensive patient’s assessment using common markers of patient’s general status, liver damage and function and HCC biology. Further studies are required to test its accuracy and provide external validation. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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12 pages, 1054 KiB

Open AccessArticle

Sustained Complete Response after Biological Downstaging in Patients with Hepatocellular Carcinoma: XXL-Like Prioritization for Liver Transplantation or “Wait and See” Strategy?

by Alessandro Vitale, Federica Scolari, Alessandra Bertacco, Enrico Gringeri, Francesco D’Amico, Domenico Bassi, Francesco Enrico D’Amico, Paolo Angeli, Patrizia Burra, Quirino Lai and Umberto Cillo

Cancers 2021, 13(10), 2406; https://doi.org/10.3390/cancers13102406 - 17 May 2021

Cited by 8 | Viewed by 2403

Abstract

The XXL trial represents the first prospective validation of “biological downstaging” in liver transplantation (LT) for hepatocellular carcinoma. The aim of this study was to compare the Padua downstaging protocol to the XXL protocol in terms of downstaging failure rates and patient outcome. [...] Read more.

The XXL trial represents the first prospective validation of “biological downstaging” in liver transplantation (LT) for hepatocellular carcinoma. The aim of this study was to compare the Padua downstaging protocol to the XXL protocol in terms of downstaging failure rates and patient outcome. A total of 191 patients undergoing aggressive surgical downstaging and potentially eligible for LT from 2012 to 2018 at our center were retrospectively selected according to XXL trial criteria. Unlike the XXL trial, patients with a complete response to downstaging did not receive any prioritization for LT. Downstaging failure was defined as stable progressive disease or post-treatment mortality. The statistical method of “matching-adjusted indirect comparison” was used to match the study group to the XXL population. Downstaging failure rate was considerably lower in the study group than in the XXL trial (12% vs. 32%, d value = |0.683|). The survival curves of our LT group (n = 68) overlapped with those of the LT-XXL group (p = 0.846). Survival curves of non-LT candidates with a sustained complete response (n = 64) were similar to those of transplanted patients (p = 0.281). Our study represents a validation of the current Padua and Italian policies of denying rapid prioritization to patients with complete response to downstaging. Such a policy seems to spare organs without worsening patient outcome. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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11 pages, 9997 KiB

Open AccessArticle

Skeletal Muscle Volume Is an Independent Predictor of Survival after Sorafenib Treatment Failure for Hepatocellular Carcinoma

by Issei Saeki, Takahiro Yamasaki, Yurika Yamauchi, Taro Takami, Tomokazu Kawaoka, Shinsuke Uchikawa, Akira Hiramatsu, Hiroshi Aikata, Reo Kawano, Kazufumi Kobayashi, Takayuki Kondo, Sadahisa Ogasawara, Tetsuhiro Chiba, Kazuaki Chayama, Naoya Kato and Isao Sakaida

Cancers 2021, 13(9), 2247; https://doi.org/10.3390/cancers13092247 - 7 May 2021

Cited by 8 | Viewed by 2098

Abstract

Few studies exist on the relationship between post-progression survival (PPS) and skeletal muscle volume in hepatocellular carcinoma (HCC) patients receiving sorafenib. This study aimed to analyze the effects of muscle volume on clinical outcomes. We retrospectively enrolled 356 HCC patients. Various clinical parameters, [...] Read more.

Few studies exist on the relationship between post-progression survival (PPS) and skeletal muscle volume in hepatocellular carcinoma (HCC) patients receiving sorafenib. This study aimed to analyze the effects of muscle volume on clinical outcomes. We retrospectively enrolled 356 HCC patients. Various clinical parameters, including skeletal muscle index, were analyzed as predictors of overall survival (OS), progression-free survival (PFS), and PPS. Patients with high muscle volume showed longer survival or PPS than those with low muscle volume (median survival time: 12.8 vs. 9.5 months, p = 0.005; median PPS: 8.2 vs. 6.3 months, p = 0.015); however, no differences in PFS were found. Multivariate analysis indicated that muscle volume was an independent predictor of PPS and OS. Skeletal muscle volume was a PPS predictor in HCC patients receiving sorafenib. Therefore, survival can be prolonged by the upregulation of skeletal muscle volume, especially in HCC patients with skeletal muscle depletion. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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20 pages, 6327 KiB

Open AccessArticle

Modeling Hepatocellular Carcinoma Cells Dynamics by Serological and Imaging Biomarkers to Explain the Different Responses to Sorafenib and Regorafenib

by Piero Colombatto, Coskun Ozer Demirtas, Gabriele Ricco, Luigi Civitano, Piero Boraschi, Paola Scalise, Daniela Cavallone, Filippo Oliveri, Veronica Romagnoli, Patrizia Bleve, Barbara Coco, Antonio Salvati, Lucio Urbani, Ferruccio Bonino and Maurizia Rossana Brunetto

Cancers 2021, 13(9), 2064; https://doi.org/10.3390/cancers13092064 - 25 Apr 2021

Cited by 4 | Viewed by 2281

Abstract

In advanced HCC, tyrosine-kinase inhibitors obtain partial responses (PR) in some patients and complete responses (CR) in a few. Better understanding of the mechanism of response could be achieved by the radiomic approach combining digital imaging and serological biomarkers (α-fetoprotein, AFP and protein [...] Read more.

In advanced HCC, tyrosine-kinase inhibitors obtain partial responses (PR) in some patients and complete responses (CR) in a few. Better understanding of the mechanism of response could be achieved by the radiomic approach combining digital imaging and serological biomarkers (α-fetoprotein, AFP and protein induced by vitamin K absence-II, PIVKA-II) kinetics. A physic-mathematical model was developed to investigate cancer cells and vasculature dynamics in three prototype patients receiving sorafenib and/or regorafenib and applied in seven others for validation. Overall four patients showed CR, two PR, two stable-disease (SD) and two progressive-disease (PD). The rate constant of cancer cells production was higher in PD than in PR-SD and CR (median: 0.398 vs. 0.325 vs. 0.316 C × day⁻¹). Therapy induced reduction of neo-angiogenesis was greater in CR than in PR-SD and PD (median: 83.2% vs. 29.4% and 2.0%), as the reduction of cell-proliferation (55.2% vs. 7.6% and 0.7%). An additional dose-dependent acceleration of tumor vasculature decay was also observed in CR. AFP and cancer cells followed the same kinetics, whereas PIVKA-II time/dose dependent fluctuations were influenced also by tissue ischemia. In conclusion, pending confirmation in a larger HCC cohort, modeling serological and imaging biomarkers could be a new tool for systemic therapy personalization. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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17 pages, 3722 KiB

Open AccessArticle

Percutaneous Irreversible Electroporation for Treatment of Small Hepatocellular Carcinoma Invisible on Unenhanced CT: A Novel Combined Strategy with Prior Transarterial Tumor Marking

by Feng Pan, Thuy D. Do, Dominik F. Vollherbst, Philippe L. Pereira, Götz M. Richter, Michael Faerber, Karl H. Weiss, Arianeb Mehrabi, Hans U. Kauczor and Christof M. Sommer

Cancers 2021, 13(9), 2021; https://doi.org/10.3390/cancers13092021 - 22 Apr 2021

Cited by 4 | Viewed by 2100

Abstract

Introduction. To explore the feasibility, safety, and efficiency of ethiodized oil tumor marking combined with irreversible electroporation (IRE) for small hepatocellular carcinomas (HCCs) that were invisible on unenhanced computed tomography (CT). Methods. A retrospective analysis of the institutional database was performed from January [...] Read more.

Introduction. To explore the feasibility, safety, and efficiency of ethiodized oil tumor marking combined with irreversible electroporation (IRE) for small hepatocellular carcinomas (HCCs) that were invisible on unenhanced computed tomography (CT). Methods. A retrospective analysis of the institutional database was performed from January 2018 to September 2018. Patients undergoing ethiodized oil tumor marking to improve target-HCC visualization in subsequent CT-guided IRE were retrieved. Target-HCC visualization after marking was assessed, and the signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNR) were compared between pre-marking and post-marking CT images using the paired t-test. Standard IRE reports, adverse events, therapeutic endpoints, and survival were summarized and assessed. Results. Nine patients with 11 target-HCCs (11.1–18.8 mm) were included. After marking, all target-HCCs demonstrated complete visualization in post-marking CT, which were invisible in pre-marking CT. Quantitatively, the SNR of the target-HCCs significantly increased after marking (11.07 ± 4.23 vs. 3.36 ± 1.79, p = 0.006), as did the CNR (4.32 ± 3.31 vs. 0.43 ± 0.28, p = 0.023). In sequential IRE procedures, the average current was 30.1 ± 5.3 A, and both the delta ampere and percentage were positive with the mean values of 5.8 ± 2.1 A and 23.8 ± 6.3%, respectively. All procedures were technically successful without any adverse events. In the follow-up, no residual unablated tumor (endpoint-1) was observed. The half-year, one-year, and two-year local tumor progression (endpoint-2) rate was 0%, 9.1%, and 27.3%. The two-year overall survival rate was 100%. Conclusions. Ethiodized oil tumor marking enables to demarcate small HCCs that were invisible on unenhanced CT. It potentially allows a safe and complete ablation in subsequent CT-guided IRE. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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14 pages, 3572 KiB

Open AccessArticle

Influence of Hepatocellular Carcinoma on Platelet Aggregation in Cirrhosis

by Alberto Zanetto, Marco Senzolo, Elena Campello, Cristiana Bulato, Sabrina Gavasso, Sarah Shalaby, Martina Gambato, Alessandro Vitale, Umberto Cillo, Fabio Farinati, Francesco Paolo Russo, Paolo Simioni and Patrizia Burra

Cancers 2021, 13(5), 1150; https://doi.org/10.3390/cancers13051150 - 8 Mar 2021

Cited by 25 | Viewed by 2286

Abstract

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 [...] Read 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 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. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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17 pages, 989 KiB

Open AccessArticle

Surveillance as Determinant of Long-Term Survival in Non-Transplanted Hepatocellular Carcinoma Patients

by Filippo Pelizzaro, Alessandro Vitale, Anna Sartori, Andrea Vieno, Barbara Penzo, Francesco Paolo Russo, Anna Chiara Frigo, Edoardo G Giannini, Manuela Piccinnu, Gian Ludovico Rapaccini, Maria Di Marco, Eugenio Caturelli, Marco Zoli, Rodolfo Sacco, Ciro Celsa, Fabio Marra, Andrea Mega, Maria Guarino, Antonio Gasbarrini, Gianluca Svegliati-Baroni, Francesco Giuseppe Foschi, Andrea Olivani, Alberto Masotto, Pietro Coccoli, Giovanni Raimondo, Francesco Azzaroli, Gianpaolo Vidili, Maurizia Rossana Brunetto, Franco Trevisani, Fabio Farinati and on behalf of ITA.LI.CA Study Group Show full author list Hide full author list

Cancers 2021, 13(4), 897; https://doi.org/10.3390/cancers13040897 - 20 Feb 2021

Cited by 9 | Viewed by 2251

Abstract

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 [...] Read 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 compared to the survival of not surveilled patients (p < 0.0001 and p = 0.0008, respectively). In IPW adjusted populations, no survival differences were demonstrated between the two groups (p = 0.30). Conclusions: Surveillance, increasing early-stage diagnosis and applicability of curative treatments, is a fundamental determinant of long-term survival in HCC patients. A wide implementation of surveillance programs should be pursued in order to improve HCC patients’ prognosis. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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12 pages, 1227 KiB

Open AccessArticle

Synergistic Impact of Alpha-Fetoprotein and Tumor Burden on Long-Term Outcomes Following Curative-Intent Resection of Hepatocellular Carcinoma

by Diamantis I. Tsilimigras, J. Madison Hyer, Adrian Diaz, Fabio Bagante, Francesca Ratti, Hugo P. Marques, Olivier Soubrane, Vincent Lam, George A. Poultsides, Irinel Popescu, Sorin Alexandrescu, Guillaume Martel, Aklile Workneh, Alfredo Guglielmi, Tom Hugh, Luca Aldrighetti, Itaru Endo and Timothy M. Pawlik

Cancers 2021, 13(4), 747; https://doi.org/10.3390/cancers13040747 - 11 Feb 2021

Cited by 27 | Viewed by 2406

Abstract

Introduction: The prognostic role of tumor burden score (TBS) relative to pre-operative α -fetoprotein (AFP) levels among patients undergoing curative-intent resection of HCC has not been examined. Methods: Patients who underwent curative-intent resection of HCC between 2000 and 2017 were identified from a [...] Read more.

Introduction: The prognostic role of tumor burden score (TBS) relative to pre-operative α -fetoprotein (AFP) levels among patients undergoing curative-intent resection of HCC has not been examined. Methods: Patients who underwent curative-intent resection of HCC between 2000 and 2017 were identified from a multi-institutional database. The impact of TBS on overall survival (OS) and cumulative recurrence relative to serum AFP levels was assessed. Results: Among 898 patients, 233 (25.9%) patients had low TBS, 572 (63.7%) had medium TBS and 93 (10.4%) had high TBS. Both TBS (5-year OS; low TBS: 76.9%, medium TBS: 60.9%, high TBS: 39.1%) and AFP (>400 ng/mL vs. <400 ng/mL: 48.5% vs. 66.1%) were strong predictors of outcomes (both p < 0.001). Lower TBS was associated with better OS among patients with both low (5-year OS, low–medium TBS: 68.0% vs. high TBS: 47.7%, p < 0.001) and high AFP levels (5-year OS, low–medium TBS: 53.7% vs. high TBS: not reached, p < 0.001). Patients with low–medium TBS/high AFP had worse OS compared with individuals with low–medium TBS/low AFP (5-year OS, 53.7% vs. 68.0%, p = 0.003). Similarly, patients with high TBS/high AFP had worse outcomes compared with patients with high TBS/low AFP (5-year OS, not reached vs. 47.7%, p = 0.015). Patients with high TBS/low AFP and low TBS/high AFP had comparable outcomes (5-year OS, 47.7% vs. 53.7%, p = 0.24). The positive predictive value of certain TBS groups relative to the risk of early recurrence and 5-year mortality after HCC resection increased with higher AFP levels. Conclusion: Both TBS and serum AFP were important predictors of prognosis among patients with resectable HCC. Serum AFP and TBS had a synergistic impact on prognosis following HCC resection with higher serum AFP predicting worse outcomes among patients with HCC of a certain TBS class. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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23 pages, 50740 KiB

Open AccessArticle

Key Enzymes in Pyrimidine Synthesis, CAD and CPS1, Predict Prognosis in Hepatocellular Carcinoma

by Dirk Andreas Ridder, Mario Schindeldecker, Arndt Weinmann, Kristina Berndt, Lana Urbansky, Hagen Roland Witzel, Stefan Heinrich, Wilfried Roth and Beate Katharina Straub

Cancers 2021, 13(4), 744; https://doi.org/10.3390/cancers13040744 - 11 Feb 2021

Cited by 34 | Viewed by 3859

Abstract

Patients with hepatocellular carcinoma (HCC) have a highly variable clinical course. Therefore, there is an urgent need to identify new prognostic markers to determine prognosis and select specific therapies. Recently, it has been demonstrated that dysregulation of the urea cycle (UC) is a [...] Read more.

Patients with hepatocellular carcinoma (HCC) have a highly variable clinical course. Therefore, there is an urgent need to identify new prognostic markers to determine prognosis and select specific therapies. Recently, it has been demonstrated that dysregulation of the urea cycle (UC) is a common phenomenon in multiple types of cancer. Upon UC dysregulation, nitrogen is diverted toward the multifunctional enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD), and increases pyrimidine synthesis. In this study, we investigated the role of CAD and carbamoyl-phosphate synthetase 1 (CPS1), a rate-limiting enzyme of the UC highly expressed in hepatocytes, in HCC. We created a tissue microarray to analyze expression of both enzymes by immunohistochemistry in a large and well-characterized overall cohort of 871 HCCs of 561 patients that underwent surgery. CAD was induced in recurrent HCCs, and high expression predicted shorter overall survival. CPS1 was downregulated in HCC and further reduced in recurrent tumors and distant metastases. Additionally, low CPS1 was associated with short overall survival. A combined score of both enzymes was an independent prognostic marker in a multivariate Cox regression model (HR = 1.37, 95% confidence interval 1.06–1.75, p = 0.014). Inhibition of pyrimidine synthesis may represent a novel therapeutic strategy for HCC. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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18 pages, 2321 KiB

Open AccessArticle

Shorter Survival after Liver Pedicle Clamping in Patients Undergoing Liver Resection for Hepatocellular Carcinoma Revealed by a Systematic Review and Meta-Analysis

by Charles-Henri Wassmer, Beat Moeckli, Thierry Berney, Christian Toso and Lorenzo A. Orci

Cancers 2021, 13(4), 637; https://doi.org/10.3390/cancers13040637 - 5 Feb 2021

Cited by 6 | Viewed by 2231

Abstract

Liver pedicle clamping minimizes surgical bleeding during hepatectomy. However, by inducing ischemia-reperfusion injury to the remnant liver, pedicle clamping may be associated with tumor recurrence in the regenerating liver. Hepatocellular carcinoma (HCC) having a high rate of recurrence, evidences demonstrating an eventual association [...] Read more.

Liver pedicle clamping minimizes surgical bleeding during hepatectomy. However, by inducing ischemia-reperfusion injury to the remnant liver, pedicle clamping may be associated with tumor recurrence in the regenerating liver. Hepatocellular carcinoma (HCC) having a high rate of recurrence, evidences demonstrating an eventual association with pedicle clamping is strongly needed. We did a systematic review of the literature until April 2020, looking at studies reporting the impact of liver pedicle clamping on long-term outcomes in patients undergoing liver resection for HCC. Primary and secondary outcomes were overall survival (OS) and disease-free survival, respectively. Results were obtained by random-effect meta-analysis and expressed as standardized mean difference (SMD). Eleven studies were included, accounting for 8087 patients. Results of seven studies were pooled in a meta-analysis. Findings indicated that, as compared to control patients who did not receive liver pedicle clamping, those who did had a significantly shorter OS (SMD = −0.172, 95%CI: −0.298 to −0.047, p = 0.007, I² = 76.8%) and higher tumor recurrence rates (odds ratio 1.36 1.01 to 1.83. p = 0.044, I² = 50.7%). This meta-analysis suggests that liver pedicle clamping may have a deleterious impact on long-term outcomes. An individual patient-data meta-analysis of randomized trials evaluating liver pedicle clamping is urgently needed. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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14 pages, 3656 KiB

Open AccessArticle

Clinical and Molecular-Based Approach in the Evaluation of Hepatocellular Carcinoma Recurrence after Radical Liver Resection

by Salvatore Gruttadauria, Floriana Barbera, Pier Giulio Conaldi, Duilio Pagano, Rosa Liotta, Enrico Gringeri, Roberto Miraglia, Gaetano Burgio, Marco Barbara, Giada Pietrosi, Calogero Cammà and Fabrizio Di Francesco

Cancers 2021, 13(3), 518; https://doi.org/10.3390/cancers13030518 - 29 Jan 2021

Cited by 7 | Viewed by 2606

Abstract

Background: Hepatic resection remains the treatment of choice for patients with early-stage HCC with preserved liver function. Unfortunately, however, the majority of patients develop tumor recurrence. While several clinical factors were found to be associated with tumor recurrence, HCC pathogenesis is a complex [...] Read more.

Background: Hepatic resection remains the treatment of choice for patients with early-stage HCC with preserved liver function. Unfortunately, however, the majority of patients develop tumor recurrence. While several clinical factors were found to be associated with tumor recurrence, HCC pathogenesis is a complex process of accumulation of somatic genomic alterations, which leads to a huge molecular heterogeneity that has not been completely understood. The aim of this study is to complement potentially predictive clinical and pathological factors with next-generation sequencing genomic profiling and loss of heterozygosity analysis. Methods: 124 HCC patients, who underwent a primary hepatic resection from January 2016 to December 2019, were recruited for this study. Next-generation sequencing (NGS) analysis and allelic imbalance assessment in a case-control subgroup analysis were performed. A time-to-recurrence analysis was performed as well by means of Kaplan–Meier estimators. Results: Cumulative number of HCC recurrences were 26 (21%) and 32 (26%), respectively, one and two years after surgery. Kaplan–Meier estimates for the probability of recurrence amounted to 37% (95% C.I.: 24–47) and to 51% (95% C.I.: 35–62), after one and two years, respectively. Multivariable analysis identified as independent predictors of HCC recurrence: hepatitis C virus (HCV) infection (HR: 1.96, 95%C.I.: 0.91–4.24, p = 0.085), serum bilirubin levels (HR: 5.32, 95%C.I.: 2.07–13.69, p = 0.001), number of nodules (HR: 1.63, 95%C.I.: 1.12–2.38, p = 0.011) and size of the larger nodule (HR: 1.11, 95%C.I.: 1.03–1.18, p = 0.004). Time-to-recurrence analysis showed that loss of heterozygosity in the PTEN loci (involved in the PI3K/AKT/mTOR signaling pathway) was significantly associated with a lower risk of HCC recurrence (HR: 0.35, 95%C.I.: 0.13–0.93, p = 0.036). Conclusions: multiple alterations of cancer genes are associated with HCC progression. In particular, the evidence of a specific AI mutation presented in 20 patients seemed to have a protective effect on the risk of HCC recurrence. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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12 pages, 1663 KiB

Open AccessArticle

Alternating Lenvatinib and Trans-Arterial Therapy Prolongs Overall Survival in Patients with Inter-Mediate Stage HepatoCellular Carcinoma: A Propensity Score Matching Study

by Shigeo Shimose, Hideki Iwamoto, Masatoshi Tanaka, Takashi Niizeki, Tomotake Shirono, Yu Noda, Naoki Kamachi, Shusuke Okamura, Masahito Nakano, Hideya Suga, Taizo Yamaguchi, Takumi Kawaguchi, Ryoko Kuromatsu, Kazunori Noguchi, Hironori Koga and Takuji Torimura

Cancers 2021, 13(1), 160; https://doi.org/10.3390/cancers13010160 - 5 Jan 2021

Cited by 44 | Viewed by 5698

Abstract

We aimed to evaluate the impact of alternating lenvatinib (LEN) and trans-arterial therapy (AT) in patients with intermediate-stage hepatocellular carcinoma (HCC) after propensity score matching (PSM). This retrospective study enrolled 113 patients with intermediate-stage HCC treated LEN. Patients were classified into the AT [...] Read more.

We aimed to evaluate the impact of alternating lenvatinib (LEN) and trans-arterial therapy (AT) in patients with intermediate-stage hepatocellular carcinoma (HCC) after propensity score matching (PSM). This retrospective study enrolled 113 patients with intermediate-stage HCC treated LEN. Patients were classified into the AT (n = 41) or non-AT group (n = 72) according to the post LEN treatment. Overall survival (OS) was calculated using the Kaplan–Meier method and analyzed using a log-rank test after PSM. Factors associated with AT were evaluated using a decision tree analysis. After PSM, there were no significant differences in age, sex, etiology, or albumin-bilirubin (ALBI) score/grade between groups. The survival rate of the AT group was significantly higher than that of the non-AT group (median survival time; not reached vs. 16.3 months, P = 0.01). Independent factors associated with OS were AT and ALBI grade 1 in the Cox regression analysis. In the decision tree analysis, age and ALBI were the first and second splitting variables for AT. In this study, we show that AT may improve prognosis in patients with intermediate-stage HCC. Moreover, alternating LEN and trans-arterial therapy may be recommended for patients below 70 years of age with ALBI grade 1. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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14 pages, 2248 KiB

Open AccessArticle

Performance of Comprehensive Complication Index and Clavien-Dindo Complication Scoring System in Liver Surgery for Hepatocellular Carcinoma

by Alessandro Giani, Federica Cipriani, Simone Famularo, Matteo Donadon, Davide Paolo Bernasconi, Francesco Ardito, Federico Fazio, Daniele Nicolini, Pasquale Perri, Mario Giuffrida, Nicholas Pontarolo, Matteo Zanello, Quirino Lai, Simone Conci, Sarah Molfino, Paola Germani, Enrico Pinotti, Maurizio Romano, Giuliano La Barba, Cecilia Ferrari, Stefan Patauner, Alberto Manzoni, Ivano Sciannamea, Luca Fumagalli, Albert Troci, Valentina Ferraro, Antonio Floridi, Fabrizio Romano, Cristina Ciulli, Marco Braga, Francesca Ratti, Guido Costa, Francesco Razionale, Nadia Russolillo, Laura Marinelli, Valerio De Peppo, Elena Cremaschi, Francesco Calabrese, Zoe Larghi Laureiro, Giovanni Lazzari, Davide Cosola, Mauro Montuori, Luca Salvador, Alessandro Cucchetti, Angelo Franceschi, Michele Ciola, Valentina Sega, Pietro Calcagno, Luca Pennacchi, Michele Tedeschi, Riccardo Memeo, Michele Crespi, Marco Chiarelli, Adelmo Antonucci, Giuseppe Zimmitti, Antonio Frena, Andrea Percivale, Giorgio Ercolani, Giacomo Zanus, Mauro Zago, Paola Tarchi, Gian Luca Baiocchi, Andrea Ruzzenente, Massimo Rossi, Elio Jovine, Marcello Maestri, Raffaele Dalla Valle, Gian Luca Grazi, Marco Vivarelli, Alessandro Ferrero, Felice Giuliante, Guido Torzilli, Luca Aldrighetti and Luca Gianotti Show full author list Hide full author list

Cancers 2020, 12(12), 3868; https://doi.org/10.3390/cancers12123868 - 21 Dec 2020

Cited by 17 | Viewed by 4302

Abstract

Background: We aimed to assess the ability of comprehensive complication index (CCI) and Clavien-Dindo complication (CDC) scale to predict excessive length of hospital stay (e-LOS) in patients undergoing liver resection for hepatocellular carcinoma. Methods: Patients were identified from an Italian multi-institutional database and [...] Read more.

Background: We aimed to assess the ability of comprehensive complication index (CCI) and Clavien-Dindo complication (CDC) scale to predict excessive length of hospital stay (e-LOS) in patients undergoing liver resection for hepatocellular carcinoma. Methods: Patients were identified from an Italian multi-institutional database and randomly selected to be included in either a derivation or validation set. Multivariate logistic regression models and ROC curve analysis including either CCI or CDC as predictors of e-LOS were fitted to compare predictive performance. E-LOS was defined as a LOS longer than the 75th percentile among patients with at least one complication. Results: A total of 2669 patients were analyzed (1345 for derivation and 1324 for validation). The odds ratio (OR) was 5.590 (95%CI 4.201; 7.438) for CCI and 5.507 (4.152; 7.304) for CDC. The AUC was 0.964 for CCI and 0.893 for CDC in the derivation set and 0.962 vs. 0.890 in the validation set, respectively. In patients with at least two complications, the OR was 2.793 (1.896; 4.115) for CCI and 2.439 (1.666; 3.570) for CDC with an AUC of 0.850 and 0.673, respectively in the derivation cohort. The AUC was 0.806 for CCI and 0.658 for CDC in the validation set. Conclusions: When reporting postoperative morbidity in liver surgery, CCI is a preferable scale. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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19 pages, 2044 KiB

Open AccessArticle

Liver Function Changes in Patients with Hepatocellular Carcinoma Treated with Lenvatinib: Predictive Factors of Progression to Child-Pugh Class B, the Formation of Ascites and the Candidates for the Post-Progression Treatment

by Takeshi Hatanaka, Satoru Kakizaki, Tamon Nagashima, Masashi Namikawa, Takashi Ueno, Hiroki Tojima, Daichi Takizawa, Atsushi Naganuma, Hirotaka Arai, Ken Sato, Norifumi Harimoto, Ken Shirabe and Toshio Uraoka

Cancers 2020, 12(10), 2906; https://doi.org/10.3390/cancers12102906 - 10 Oct 2020

Cited by 18 | Viewed by 2749

Abstract

The aim of this multicenter retrospective study was to assess the change in liver function in patients with hepatocellular carcinoma treated with lenvatinib. Among 139 consecutive patients receiving lenvatinib treatment between March 2018 and July 2019, 28 patients with Child-Pugh class B and [...] Read more.

The aim of this multicenter retrospective study was to assess the change in liver function in patients with hepatocellular carcinoma treated with lenvatinib. Among 139 consecutive patients receiving lenvatinib treatment between March 2018 and July 2019, 28 patients with Child-Pugh class B and one patient with inadequate patient information were excluded. Remaining 110 patients with Child-Pugh class A were analyzed. The median age of 110 patients was 73 years (IQR 66.7–80) and 88 patients (80.0%) were men. Child-Pugh score was 5 (CP5A) and 6 (CP6A) in 58 (52.7%) and 52 patients (47.3%), and ALBI grade was 1 and 2 in 38 (34.5%) and 72 patients (65.5%), respectively. The deterioration to Child-Pugh class B was found in 43 patients (39.1%) during the lenvatinib treatment. The favorable factors related to preserving liver function were significantly shown to be male, ALBI grade 1, CP5A and BCLC early or intermediate stage in the multivariate analysis. The formation of ascites was found in 32 patients (28.6%). The significant unfavorable factors associated with the formation of ascites were found to be low platelet count and CP6A. Among the 79 patients, there were 36 (45.6%) and 11 patients (13.9%) who fulfilled the criteria for candidate for the post-progression treatment and ramucirumab treatment, respectively. The predictive factors of the post-progression treatment were shown to be ALBI grade 1 and CP5A in multivariate analysis. In conclusion, male, ALBI grade 1, CP5A and BCLC early or intermediate stage were favorable factors related to sustaining liver function and the patients with ALBI grade 1 and CP5A were eligible for the post-progression treatment. Careful screening for ascites was needed in patients with low platelet count and CP6A. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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16 pages, 1639 KiB

Open AccessArticle

How Should We Assign Large Infiltrative Hepatocellular Carcinomas for Staging?

by Yoo Jin Lee, Yoo Ra Lee, Chung Gyo Seo, Hyun Gil Goh, Tae Hyung Kim, Sun Young Yim, Na Yeon Han, Jae Min Lee, Hyuk Soon Choi, Eun Sun Kim, Bora Keum, Hyonggin An, Beomjin Park, Yeon Seok Seo, Hyung Joon Yim, Ji Hoon Kim, Young Dong Yu, Dong Sik Kim, Yoon Tae Jeen, Hoon Jai Chun, Hong Sik Lee, Chang Duck Kim and Soon Ho Um Show full author list Hide full author list

Cancers 2020, 12(9), 2589; https://doi.org/10.3390/cancers12092589 - 10 Sep 2020

Cited by 7 | Viewed by 2749

Abstract

Infiltrative gross morphology of hepatocellular carcinoma (HCC) is known to be associated with poor prognosis, but this is not considered for staging. A total of 774 HCC patients who underwent curative liver resection were retrospectively reviewed and the prognostic significance of infiltrative type [...] Read more.

Infiltrative gross morphology of hepatocellular carcinoma (HCC) is known to be associated with poor prognosis, but this is not considered for staging. A total of 774 HCC patients who underwent curative liver resection were retrospectively reviewed and the prognostic significance of infiltrative type HCC was assessed using the American Joint Committee on Cancer (AJCC) and Barcelona Clinic Liver Cancer (BCLC) staging systems. Seventy-four patients (9.6%) had infiltrative HCCs with a higher proportion of multifocal tumors, larger tumors, vessel invasion, increased tumor marker levels, and advanced T-stages than those with nodular HCC (all, p < 0.01). Infiltrative morphology was independently associated with lower overall survival (OS), but its impact was significant when the tumor size was ≥ 4 cm (p < 0.001). Under current AJCC and BCLC staging criteria, these large infiltrative HCCs were associated with significantly worse OS in early AJCC T-stages (T1b/T2, p < 0.001) and BCLC stage A/B (both, p < 0.01) but not in late AJCC (T3/T4) and BCLC C. The reassignment of this subtype to T3 and T4 increased the discriminatory ability of AJCC T-staging with lower AIC values (3090 and 3088 vs. 3109) and higher c-index (0.69 and 0.69 vs. 0.67), respectively (both, p < 0.001). Similarly, the reassignment of large infiltrative HCC to BCLC stages B and C also improved the prognostic performance. Large infiltrative HCCs should be assigned to more advanced stages in current staging systems for their prognostic impact. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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13 pages, 1460 KiB

Open AccessArticle

Survival of Patients with Hepatocellular Carcinoma in Renal Insufficiency: Prognostic Role of Albumin-Bilirubin Grade

by Shu-Yein Ho, Chia-Yang Hsu, Po-Hong Liu, Chih-Chieh Ko, Yi-Hsiang Huang, Chien-Wei Su, Rheun-Chuan Lee, Ming-Chih Hou and Teh-Ia Huo

Cancers 2020, 12(5), 1130; https://doi.org/10.3390/cancers12051130 - 30 Apr 2020

Cited by 10 | Viewed by 2407

Abstract

Renal insufficiency (RI) is commonly seen in patients with hepatocellular carcinoma (HCC). The prognostic role of albumin-bilirubin (ALBI) grade in this special setting is unclear. We aimed to investigate the role of ALBI grade associated with the impact of RI on HCC. A [...] Read more.

Renal insufficiency (RI) is commonly seen in patients with hepatocellular carcinoma (HCC). The prognostic role of albumin-bilirubin (ALBI) grade in this special setting is unclear. We aimed to investigate the role of ALBI grade associated with the impact of RI on HCC. A prospective cohort of 3690 HCC patients between 2002 and 2016 were retrospectively analyzed. The Kaplan–Meier method and multivariate Cox proportional hazards model were used to determine survival and independent prognostic predictors. Of all patients, RI was an independent predictor associated with decreased survival. In multivariate Cox analysis for patients with RI, α-fetoprotein level ≥20 ng/mL, tumor size >3 cm, vascular invasion, distant metastasis, presence of ascites, performance status 1–2, performance status 3–4, and ALBI grade 2 and grade 3 were independent predictors of decreased survival (all p < 0.05). In subgroup analysis of patients with RI undergoing curative and non-curative treatments, the ALBI grade remained a significant prognostic predictor associated with decreased survival (p < 0.001). In summary, HCC patients with RI have decreased survival compared to those without RI. The ALBI grade can discriminate the survival in patients with RI independent of treatment strategy and is a feasible prognostic tool in this special patient population. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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Review

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23 pages, 9017 KiB

Open AccessReview

Overview of Prognostic Systems for Hepatocellular Carcinoma and ITA.LI.CA External Validation of MESH and CNLC Classifications

by Alessandro Vitale, Fabio Farinati, Michele Finotti, Chiara Di Renzo, Giuseppina Brancaccio, Fabio Piscaglia, Giuseppe Cabibbo, Eugenio Caturelli, Gabriele Missale, Fabio Marra, Rodolfo Sacco, Edoardo G. Giannini, Franco Trevisani, Umberto Cillo, Associazione Italiana per lo Studio del Fegato (AISF) HCC Special Interest Group and Italian Liver Cancer (ITA.LI.CA) Study Group

Cancers 2021, 13(7), 1673; https://doi.org/10.3390/cancers13071673 - 2 Apr 2021

Cited by 25 | Viewed by 3396

Abstract

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 [...] Read 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 first on an overview of the main prognostic systems for HCC classified according to the above three categories, and, second, on a comprehensive description of the methodology required for a correct comparison between different systems in terms of prognostic performance. In this second section the main studies in the literature comparing different prognostic systems are described in detail. Lastly, a formal comparison between the last prognostic systems proposed for each of the above three categories is performed using a large Italian database including 6882 HCC patients in order to concretely apply the comparison rules previously described. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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18 pages, 2274 KiB

Open AccessReview

Immunmodulatory Treatment Strategies of Hepatocellular Carcinoma: From Checkpoint Inhibitors Now to an Integrated Approach in the Future

by Matthias Ocker, Christian Mayr, Tobias Kiesslich, Sebastian Stintzing and Daniel Neureiter

Cancers 2021, 13(7), 1558; https://doi.org/10.3390/cancers13071558 - 29 Mar 2021

Cited by 8 | Viewed by 3676

Abstract

Background: Hepatocellular carcinoma (HCC) still represents a human tumor entity with very limited therapeutic options, especially for advanced stages. Here, immune checkpoint modulating drugs alone or in combination with local ablative techniques could open a new and attractive therapeutic “door” to improve outcome [...] Read more.

Background: Hepatocellular carcinoma (HCC) still represents a human tumor entity with very limited therapeutic options, especially for advanced stages. Here, immune checkpoint modulating drugs alone or in combination with local ablative techniques could open a new and attractive therapeutic “door” to improve outcome and response rate for patients with HCC. Methods: Published data on HCC experimental to pre-(clinical) treatment strategies from standard of care to novel immunomodulatory concepts were summarized and discussed in detail. Results: Overall, our knowledge of the role of immune checkpoints in HCC is dramatically increased in the last years. Experimental and pre-clinical findings could be translated to phase 1 and 2 clinical trials and became standard of care. Local ablative techniques of HCC could improve the effectivity of immune checkpoint inhibitors in situ. Conclusions: This review demonstrates the importance of immunomodulatory treatment strategies of HCC, whereby the “best treatment code” of immune checkpoint drugs, combination with ablative techniques and of timing must be evaluated in coming clinical trials. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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17 pages, 993 KiB

Open AccessReview

The Role of Liquid Biopsy in Hepatocellular Carcinoma Prognostication

by Ismail Labgaa, Augusto Villanueva, Olivier Dormond, Nicolas Demartines and Emmanuel Melloul

Cancers 2021, 13(4), 659; https://doi.org/10.3390/cancers13040659 - 6 Feb 2021

Cited by 29 | Viewed by 4590

Abstract

Showing a steadily increasing cancer-related mortality, the epidemiological evolution of hepatocellular carcinoma (HCC) is concerning. Numerous strategies have attempted to prognosticate HCC but their performance is modest; this is partially due to the heterogeneous biology of this cancer. Current clinical guidelines endorse classifications [...] Read more.

Showing a steadily increasing cancer-related mortality, the epidemiological evolution of hepatocellular carcinoma (HCC) is concerning. Numerous strategies have attempted to prognosticate HCC but their performance is modest; this is partially due to the heterogeneous biology of this cancer. Current clinical guidelines endorse classifications and scores that use clinical variables, such as the Barcelona Clinic Liver Cancer (BCLC) classification. These algorithms are unlikely to fully recapitulate the genomic complexity of HCC. Integrating molecular readouts on a patient-basis, following a precision-medicine perspective, might be an option to refine prognostic systems. The limited access to HCC tissue samples is an important limitation to these approaches but it could be partially circumvented by using liquid biopsy. This concept consists of the molecular analysis of products derived from a solid tumor and released into biological fluids, mostly into the bloodstream. It offers an easy and minimally-invasive access to DNA, RNA, extracellular vesicles and cells that can be analyzed with next-generation sequencing (NGS) technologies. This review aims to investigate the potential contributions of liquid biopsy in HCC prognostication. The results identified prognostic values for each of the components of liquid biopsy, suggesting that this technology may help refine HCC prognostication. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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Graphical abstract

18 pages, 645 KiB

Open AccessReview

Locoregional Therapy Approaches for Hepatocellular Carcinoma: Recent Advances and Management Strategies

by Mina S. Makary, Umang Khandpur, Jordan M. Cloyd, Khalid Mumtaz and Joshua D. Dowell

Cancers 2020, 12(7), 1914; https://doi.org/10.3390/cancers12071914 - 15 Jul 2020

Cited by 81 | Viewed by 10626

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and third leading cause of cancer-related mortality worldwide. While surgical resection and transplantation are the standard first-line treatments for early-stage HCC, most patients do not fulfill criteria for surgery. Fortunately, catheter-directed and percutaneous [...] Read more.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and third leading cause of cancer-related mortality worldwide. While surgical resection and transplantation are the standard first-line treatments for early-stage HCC, most patients do not fulfill criteria for surgery. Fortunately, catheter-directed and percutaneous locoregional approaches have evolved as major treatment modalities for unresectable HCC. Improved outcomes have been achieved with novel techniques which can be employed for diverse applications ranging from curative-intent for small localized tumors, to downstaging or bridging to resection and transplantation for early and intermediate disease, and locoregional control and palliation for advanced disease. This review explores recent advances in liver-directed techniques for HCC including bland transarterial embolization, chemoembolization, radioembolization, and ablative therapies, with a focus on patient selection, procedural technique, periprocedural management, and outcomes. Full article

(This article belongs to the Special Issue Prognosis and Treatment of Hepatocellular Carcinoma)

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