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15 pages, 5084 KiB

Open AccessArticle

On Efficacy of Microwave Ablation in the Thermal Treatment of an Early-Stage Hepatocellular Carcinoma

by Branislav Radjenović, Martin Sabo, Lukaš Šoltes, Marta Prnova, Pavel Čičak and Marija Radmilović-Radjenović

Cancers 2021, 13(22), 5784; https://doi.org/10.3390/cancers13225784 - 18 Nov 2021

Cited by 17 | Viewed by 2700

Abstract

Microwave ablation at 2.45 GHz is gaining popularity as an alternative therapy to hepatic resection with a higher overall survival rate than external beam radiation therapy and proton beam therapy. It also offers better long-term recurrence-free overall survival when compared with radiofrequency ablation. [...] Read more.

Microwave ablation at 2.45 GHz is gaining popularity as an alternative therapy to hepatic resection with a higher overall survival rate than external beam radiation therapy and proton beam therapy. It also offers better long-term recurrence-free overall survival when compared with radiofrequency ablation. To improve the design and optimization of microwave ablation procedures, numerical models can provide crucial information. A three-dimensional model of the antenna and targeted tissue without homogeneity assumptions are the most realistic representation of the physical problem. Due to complexity and computational resources consumption, most of the existing numerical studies are based on using two-dimensional axisymmetric models to emulate actual three-dimensional cancers and surrounding tissue, which is often far from reality. The main goal of this study is to develop a fully three-dimensional model of a multislot microwave antenna immersed into liver tissue affected by early-stage hepatocellular carcinoma. The geometry of the tumor is taken from the 3D-IRCADb-01 liver tumors database. Simulations were performed involving the temperature dependence of the blood perfusion, dielectric and thermal properties of both healthy and tumoral liver tissues. The water content changes during the ablation process are also included. The optimal values of the input power and the ablation time are determined to ensure complete treatment of the tumor with minimal damage to the healthy tissue. It was found that a multislot antenna is designed to create predictable, large, spherical zones of the ablation that are not influenced by varying tissue environments. The obtained results may be useful for determining optimal conditions necessary for microwave ablation to be as effective as possible for treating early-stage hepatocellular carcinoma, with minimized invasiveness and collateral damages. Full article

(This article belongs to the Special Issue New Advances in Hepatocellular Carcinoma: From the Past to the Future)

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13 pages, 1591 KiB

Open AccessArticle

Minimally Invasive versus Open Liver Resection for Stage I/II Hepatocellular Carcinoma

by Emrullah Birgin, Sarah R. Kaslow, Svetlana Hetjens, Camilo Correa-Gallego and Nuh N. Rahbari

Cancers 2021, 13(19), 4800; https://doi.org/10.3390/cancers13194800 - 25 Sep 2021

Cited by 9 | Viewed by 2048

Abstract

Minimally invasive liver resection (MILR) is increasingly used as a surgical treatment for patients with hepatocellular carcinoma (HCC). However, there is no large scale data to compare the effectiveness of MILR in comparison to open liver resection (OLR). We identified patients with stage [...] Read more.

Minimally invasive liver resection (MILR) is increasingly used as a surgical treatment for patients with hepatocellular carcinoma (HCC). However, there is no large scale data to compare the effectiveness of MILR in comparison to open liver resection (OLR). We identified patients with stage I or II HCC from the National Cancer Database using propensity score matching techniques. Overall, 1931 (66%) and 995 (34%) patients underwent OLR or MILR between 2010 and 2015. After propensity matching, 5-year OS was similar in the MILR and OLR group (51.7% vs. 52.8%, p = 0.766). MILR was associated with lower 90-day mortality (5% vs. 7%, p = 0.041) and shorter length of stay (4 days vs. 5 days, p < 0.001), but higher rates of positive margins (6% vs. 4%, p = 0.001). An operation at an academic institution was identified as an independent preventive factor for a positive resection margin (OR 0.64: 95% CI 0.43–0.97) and 90-day mortality (OR 0.61; 95% CI 0.41–0.91). MILR for HCC is associated with similar overall survival to OLR, with the benefit of improved short term postoperative outcomes. The increased rate of positive margins after MILR requires further investigation, as do the differences in perioperative outcomes between academic and nonacademic institutions. Full article

(This article belongs to the Special Issue New Advances in Hepatocellular Carcinoma: From the Past to the Future)

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12 pages, 1339 KiB

Open AccessArticle

Efficacy and Safety of Lenvatinib in Hepatocellular Carcinoma Patients with Liver Transplantation: A Case-Control Study

by Yen-Yang Chen, Chao-Long Chen, Chih-Che Lin, Chih-Chi Wang, Yueh-Wei Liu, Wei-Feng Li and Yen-Hao Chen

Cancers 2021, 13(18), 4584; https://doi.org/10.3390/cancers13184584 - 12 Sep 2021

Cited by 12 | Viewed by 2778

Abstract

Tumor recurrence is the most common cause of death in hepatocellular carcinoma (HCC) patients who received liver transplantation (LT). Recently, lenvatinib was approved for the systemic treatment of unresectable HCC patients; however, the role of lenvatinib in HCC patients after LT remains unclear. [...] Read more.

Tumor recurrence is the most common cause of death in hepatocellular carcinoma (HCC) patients who received liver transplantation (LT). Recently, lenvatinib was approved for the systemic treatment of unresectable HCC patients; however, the role of lenvatinib in HCC patients after LT remains unclear. There were 56 patients with recurrent HCC after LT from 2008 to 2018 in our institute, and 10 patients who received lenvatinib were identified. Additionally, to understand the difference in the clinical impact of lenvatinib in the LT and non-LT settings, 25 HCC patients without LT who underwent lenvatinib treatment were identified from our HCC database and regarded as the control group. In the LT group, partial response was 20% and stable disease was 50%, resulting in a disease control rate of 70%; the median progression-free survival (PFS), time to treatment failure (TTF) and overall survival (OS) were 3.7, 3.6 and 16.4 months, respectively. Adverse events (AEs) were predominantly grade 1–2 in severity, and the majority of patients tolerated the side effects. There was no significant difference in PFS/OS, and we observed a similar pattern of AEs between these two groups. Our study confirms the comparable efficacy and safety of lenvatinib in HCC patients with LT and non-LT in clinical practice. Full article

(This article belongs to the Special Issue New Advances in Hepatocellular Carcinoma: From the Past to the Future)

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15 pages, 1294 KiB

Open AccessArticle

Refining Prognosis in Chemoembolization for Hepatocellular Carcinoma: Immunonutrition and Liver Function

by Lukas Müller, Felix Hahn, Aline Mähringer-Kunz, Fabian Stoehr, Simon Johannes Gairing, Friedrich Foerster, Arndt Weinmann, Peter Robert Galle, Jens Mittler, Daniel Pinto dos Santos, Michael Bernhard Pitton, Christoph Düber and Roman Kloeckner

Cancers 2021, 13(16), 3961; https://doi.org/10.3390/cancers13163961 - 5 Aug 2021

Cited by 8 | Viewed by 2199

Abstract

A combination of albumin-bilirubin (ALBI) grading and the Prognostic Nutritional Index (PNI) was identified recently as a highly predictive tool for patients with hepatocellular carcinoma (HCC) undergoing tumor ablation. The present study evaluated this combination in patients undergoing transarterial chemoembolization (TACE). Between 2010 [...] Read more.

A combination of albumin-bilirubin (ALBI) grading and the Prognostic Nutritional Index (PNI) was identified recently as a highly predictive tool for patients with hepatocellular carcinoma (HCC) undergoing tumor ablation. The present study evaluated this combination in patients undergoing transarterial chemoembolization (TACE). Between 2010 and 2020, 280 treatment-naïve patients were retrospectively identified. The influence of ALBI grade, PNI and the novel ALBI-PNI on the median overall survival (OS) was assessed. In the next step, the prognostic ability of the combined approach was compared to established scoring systems. Both ALBI grade 2−3 and a low PNI were highly predictive for median OS (ALBI grade 1–3: 39.0 vs. 16.3 vs. 5.4 months, p < 0.001; high vs. low PNI: 21.4 vs. 7.5, p < 0.001). The combination of both resulted in a median OS of 39.0, 20.1, 10.3, and 5.4 months (p < 0.001). With a Concordance Index (C-Index) of 0.69, ALBI-PNI outperformed each individual score (ALBI 0.65, PNI 0.64) and was also better than BCLC, HAP, mHAP-II, and the Six-and-Twelve score (C-Indices 0.66, 0.60, 0.59, and 0.55). Thus, the easy-to-calculate ALBI-PNI may be a promising stratification tool for patients with HCC undergoing TACE, reflecting both immunonutritive status and liver function. Full article

(This article belongs to the Special Issue New Advances in Hepatocellular Carcinoma: From the Past to the Future)

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16 pages, 5547 KiB

Open AccessArticle

Possible Role of IRS-4 in the Origin of Multifocal Hepatocellular Carcinoma

by Luis G. Guijarro, Patricia Sanmartin-Salinas, Eva Pérez-Cuevas, M. Val Toledo-Lobo, Jorge Monserrat, Sofía Zoullas, Miguel A. Sáez, Miguel A. Álvarez-Mon, Julia Bujan, Fernando Noguerales-Fraguas, Eduardo Arilla-Ferreiro, Melchor Álvarez-Mon and Miguel A. Ortega

Cancers 2021, 13(11), 2560; https://doi.org/10.3390/cancers13112560 - 23 May 2021

Cited by 10 | Viewed by 2769

Abstract

New evidence suggests that insulin receptor substrate 4 (IRS-4) may play an important role in the promotion of tumoral growth. In this investigation, we have evaluated the role of IRS-4 in a pilot study performed on patients with liver cancer. We used immunohistochemistry [...] Read more.

New evidence suggests that insulin receptor substrate 4 (IRS-4) may play an important role in the promotion of tumoral growth. In this investigation, we have evaluated the role of IRS-4 in a pilot study performed on patients with liver cancer. We used immunohistochemistry to examine IRS-4 expression in biopsies of tumoral tissue from a cohort of 31 patient suffering of hepatocellular carcinoma (HCC). We simultaneously analyzed the expression of the cancer biomarkers PCNA, Ki-67, and pH3 in the same tissue samples. The in vitro analysis was conducted by studying the behavior of HepG2 cells following IRS-4 overexpression/silencing. IRS-4 was expressed mainly in the nuclei of tumoral cells from HCC patients. In contrast, in healthy cells involved in portal triads, canaliculi, and parenchymal tissue, IRS-4 was observed in the cytosol and the membrane. Nuclear IRS-4 in the tumoral region was found in 69.9 ± 3.2%, whereas in the surrounding healthy hepatocytes, nuclear IRS-4 was rarely observed. The percentage of tumoral cells that exhibited nuclear PCNA and Ki-67 were 52.1 ± 7%, 6.1 ± 1.1% and 1.3 ± 0.2%, respectively. Furthermore, we observed a significant positive linear correlation between nuclear IRS-4 and PCNA (r = 0.989; p < 0.001). However, when we correlated the nuclear expression of IRS-4 and Ki-67, we observed a significant positive curvilinear correlation (r = 0.758; p < 0.010). This allowed us to define two populations, (IRS-4 + Ki-67 ≤ 69%) and (IRS-4 + Ki-67 > 70%). The population with lower levels of IRS-4 and Ki-67 had a higher risk of suffering from multifocal liver cancer (OR = 16.66; CI = 1.68–164.8 (95%); p < 0.05). Immunoblot analyses showed that IRS-4 in normal human liver biopsies was lower than in HepG2, Huh7, and Chang cells. Treatment of HepG2 with IGF-1 and EGF induced IRS-4 translocation to the nucleus. Regulation of IRS-4 levels via HepG2 transfection experiments revealed the protein’s role in proliferation, cell migration, and cell-collagen adhesion. Nuclear IRS-4 is increased in the tumoral region of HCC. IRS-4 and Ki-67 levels are significantly correlated with the presence of multifocal HCC. Moreover, upregulation of IRS-4 in HepG2 cells induced proliferation by a β-catenin/Rb/cyclin D mechanism, whereas downregulation of IRS-4 caused a loss in cellular polarity and in its adherence to collagen as well as a gain in migratory and invasive capacities, probably via an integrin α2 and focal adhesion cascade (FAK) mechanism. Full article

(This article belongs to the Special Issue New Advances in Hepatocellular Carcinoma: From the Past to the Future)

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13 pages, 624 KiB

Open AccessArticle

The Association between Prognostic Nutritional Index (PNI) and Intraoperative Transfusion in Patients Undergoing Hepatectomy for Hepatocellular Carcinoma: A Retrospective Cohort Study

by Ji Hoon Sim, Sung-Hoon Kim, In-Gu Jun, Sa-Jin Kang, Bomi Kim, Seonok Kim and Jun-Gol Song

Cancers 2021, 13(11), 2508; https://doi.org/10.3390/cancers13112508 - 21 May 2021

Cited by 12 | Viewed by 1726

Abstract

Background: PNI is significantly associated with surgical outcomes; however, the association between PNI and intraoperative transfusions is unknown. Methods: This study retrospectively analyzed 1065 patients who underwent hepatectomy. We divided patients into two groups according to the PNI (<44 and >44) and compared [...] Read more.

Background: PNI is significantly associated with surgical outcomes; however, the association between PNI and intraoperative transfusions is unknown. Methods: This study retrospectively analyzed 1065 patients who underwent hepatectomy. We divided patients into two groups according to the PNI (<44 and >44) and compared their transfusion rates and surgical outcomes. We performed multivariate logistic and Cox regression analysis to determine risk factors for transfusion and the 5-year survival. Additionally, we found the net reclassification index (NRI) to validate the discriminatory power of PNI. Results: The PNI <44 group had higher transfusion rates (adjusted odds ratio [OR]: 2.20, 95%CI: 1.06–4.60, p = 0.035) and poor surgical outcomes, such as post hepatectomy liver failure (adjusted [OR]: 3.02, 95%CI: 1.87–4.87, p < 0.001), and low 5-year survival (adjusted OR: 1.68, 95%CI: 1.17–2.24, p < 0.001). On multivariate analysis, PNI <44, age, hemoglobin, operation time, synthetic colloid use, and laparoscopic surgery were risk factors for intraoperative transfusion. On Cox regression analysis, PNI <44, MELD score, TNM staging, synthetic colloid use, and transfusion were associated with poorer 5-year survival. NRI analysis showed significant improvement in the predictive power of PNI for transfusion (p = 0.002) and 5-year survival (p = 0.004). Conclusions: Preoperative PNI <44 was significantly associated with higher transfusion rates and surgical outcomes. Full article

(This article belongs to the Special Issue New Advances in Hepatocellular Carcinoma: From the Past to the Future)

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15 pages, 8321 KiB

Open AccessArticle

Minimization of Immunosuppressive Therapy Is Associated with Improved Survival of Liver Transplant Patients with Recurrent Hepatocellular Carcinoma

by Ramin Raul Ossami Saidy, Maximilian Paul Postel, Michael Johannes Pflüger, Wenzel Schoening, Robert Öllinger, Safak Gül-Klein, Moritz Schmelzle, Frank Tacke, Johann Pratschke and Dennis Eurich

Cancers 2021, 13(7), 1617; https://doi.org/10.3390/cancers13071617 - 31 Mar 2021

Cited by 11 | Viewed by 1854

Abstract

Introduction: Recurrence of hepatocellular carcinoma (rHCC) after liver transplantation (LT) is associated with limited survival. Therefore, identification of factors that prolong survival in these patients is of great interest. Surgical resection, radiotherapy, and transarterial chemoembolization (TACE) are established interventions to improve outcomes in [...] Read more.

Introduction: Recurrence of hepatocellular carcinoma (rHCC) after liver transplantation (LT) is associated with limited survival. Therefore, identification of factors that prolong survival in these patients is of great interest. Surgical resection, radiotherapy, and transarterial chemoembolization (TACE) are established interventions to improve outcomes in these patients; however, the impact of immunosuppression is unknown. Methods: All patients diagnosed with rHCC in the follow-up after LT were identified from a database of liver recipients transplanted between 1988 and 2019 at our institution (Charité Universitätsmedizin Berlin, Germany). Based on the immunosuppressive regimen following diagnosis of rHCC and the oncological treatment approach, survival analysis was performed. Results: Among 484 patients transplanted for HCC, 112 (23.1%) developed rHCC in the follow-up. Recurrent HCC was diagnosed at a median interval of 16.0 months (range 1.0–203.0), with the majority presenting early after transplantation (63.0%, <2 years). Median survival after rHCC diagnosis was 10.6 months (0.3–228.7). Reduction of immunosuppression was associated with improved survival, particularly in patients with palliative treatment (8.4 versus 3.0 months). In addition, greater reduction of immunosuppression seemed to be associated with greater prolongation of survival. Graft rejection after reduction was uncommon (n = 7, 6.8%) and did not result in any graft loss. Patients that underwent surgical resection showed improved survival rates (median 19.5 vs. 8.7 months). Conclusion: Reduction of immunosuppressive therapy after rHCC diagnosis is associated with prolonged survival in LT patients. Therefore, reduction of immunosuppression should be an early intervention following diagnosis. In addition, surgical resection should be attempted, if technically feasible and oncologically meaningful. Full article

(This article belongs to the Special Issue New Advances in Hepatocellular Carcinoma: From the Past to the Future)

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Review

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33 pages, 4087 KiB

Open AccessReview

The Landscape of lncRNAs in Hepatocellular Carcinoma: A Translational Perspective

by Juan Pablo Unfried, Paloma Sangro, Laura Prats-Mari, Bruno Sangro and Puri Fortes

Cancers 2021, 13(11), 2651; https://doi.org/10.3390/cancers13112651 - 28 May 2021

Cited by 18 | Viewed by 3714

Abstract

LncRNAs are emerging as relevant regulators of multiple cellular processes involved in cell physiology as well as in the development and progression of human diseases, most notably, cancer. Hepatocellular carcinoma (HCC) is a prominent cause of cancer-related death worldwide due to the high [...] Read more.

LncRNAs are emerging as relevant regulators of multiple cellular processes involved in cell physiology as well as in the development and progression of human diseases, most notably, cancer. Hepatocellular carcinoma (HCC) is a prominent cause of cancer-related death worldwide due to the high prevalence of causative factors, usual cirrhotic status of the tumor-harboring livers and the suboptimal benefit of locoregional and systemic therapies. Despite huge progress in the molecular characterization of HCC, no oncogenic loop addiction has been identified and most genetic alterations remain non-druggable, underscoring the importance of advancing research in novel approaches for HCC treatment. In this context, long non-coding RNAs (lncRNAs) appear as potentially useful targets as they often exhibit high tumor- and tissue-specific expression and many studies have reported an outstanding dysregulation of lncRNAs in HCC. However, there is a limited perspective of the potential role that deregulated lncRNAs may play in HCC progression and aggressiveness or the mechanisms and therapeutic implications behind such effects. In this review, we offer a clarifying landscape of current efforts to evaluate lncRNA potential as therapeutic targets in HCC using evidence from preclinical models as well as from recent studies on novel oncogenic pathways that show lncRNA-dependency. Full article

(This article belongs to the Special Issue New Advances in Hepatocellular Carcinoma: From the Past to the Future)

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