Cancers

2024

Jump to: 2023, 2022, 2021, 2020

20 pages, 7201 KiB

Open AccessReview

A Pathological Assessment of the Microvasculature of Biliary Tract Neoplasms Referring to Pre-Existing Blood Vessels and Vessel Co-Option

by Yasuni Nakanuma, Zihan Li, Yasunori Sato, Motoko Sasaki, Kenichi Harada, Yuko Kakuda and Takashi Sugino

Cancers 2024, 16(22), 3869; https://doi.org/10.3390/cancers16223869 - 19 Nov 2024

Viewed by 294

Abstract

There are several types of microvasculature supplying neoplasms: “newly formed blood vessels” (neoangiogenesis), which are a component of the tumor microenvironment (TME) of invasive carcinoma with wound healing-like reaction; and “pre-existing blood vessels”, which are used as tumor-supplying vessels by neoplasms (co-option vessels) [...] Read more.

There are several types of microvasculature supplying neoplasms: “newly formed blood vessels” (neoangiogenesis), which are a component of the tumor microenvironment (TME) of invasive carcinoma with wound healing-like reaction; and “pre-existing blood vessels”, which are used as tumor-supplying vessels by neoplasms (co-option vessels) and are likely to develop in hypervascularized organs. We herein review the microvasculature of neoplasms of biliary tract with reference to pre-existing vessels and vessel co-options. In the hepatobiliary system, intrahepatic large and extrahepatic bile ducts (large bile ducts) and the gallbladder as well as hepatic lobules are highly vascularized regions. In large bile ducts, the biliary lining epithelia and underlining capillaries (peribiliary capillary plexus [PCP]) form the biliary epithelia–PCP alignment, whereas the hepatocyte–sinusoid alignment composes hepatic lobules. Cholangiocarcinoma (CCA) and gallbladder carcinoma (GBC) are the main biliary tract carcinomas. CCA is subdivided into distal (d/CCA), perihilar (pCCA), and intrahepatic (iCCA), and iCCA is subdivided into small duct type (SD-iCCA) and large duct type (LD-iCCA). High-grade biliary intraepithelial neoplasm (BilIN), intraductal papillary neoplasm of the bile duct (IPNB), pyloric gland adenoma (PGA), and intracholecystic papillary neoplasm (ICPN) have recently been proposed as the precursors of LD-iCCA, p/dCCA, and GBC. In the large bile ducts and gallbladder, all cases of high-grade BilIN and PGA, about half of IPNB, and one-third of ICPN with less-complicated structure were found to have hijacked the PCP as their supporting vessels (vessel co-option), while p/dCCA, LD-iCCA, and GBC were supplied by neo-angiogenetic vessels associated with fibrous stroma. The intraluminal components of the remaining cases of ICPN and IPNB with complicated structure presented sparse capillaries without fibrous stroma, a unique microvasculature different from that of co-option or neoangiogenesis. Regarding iCCA showing invasion into the hepatic lobules, some SD-iCCAs replaced hepatocytic cords and used pre-existing sinusoids as co-opted vessels. Visualization of pre-existing vessels could be a new pathological tool for the evaluation of malignant progression and of vascular supply in CCAs and its precursors. Full article

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18 pages, 1752 KiB

Open AccessReview

The Impact of Biliary Injury on the Recurrence of Biliary Cancer and Benign Disease after Liver Transplantation: Risk Factors and Mechanisms

by Chase J. Wehrle, Rebecca Panconesi, Sangeeta Satish, Marianna Maspero, Chunbao Jiao, Keyue Sun, Omer Karakaya, Erlind Allkushi, Jamak Modaresi Esfeh, Maureen Whitsett Linganna, Wen Wee Ma, Masato Fujiki, Koji Hashimoto, Charles Miller, David C. H. Kwon, Federico Aucejo and Andrea Schlegel

Cancers 2024, 16(16), 2789; https://doi.org/10.3390/cancers16162789 - 7 Aug 2024

Viewed by 1213

Abstract

Liver transplantation is known to generate significant inflammation in the entire organ based on the metabolic profile and the tissue’s ability to recover from the ischemia-reperfusion injury (IRI). This cascade contributes to post-transplant complications, affecting both the synthetic liver function (immediate) and the [...] Read more.

Liver transplantation is known to generate significant inflammation in the entire organ based on the metabolic profile and the tissue’s ability to recover from the ischemia-reperfusion injury (IRI). This cascade contributes to post-transplant complications, affecting both the synthetic liver function (immediate) and the scar development in the biliary tree. The new occurrence of biliary strictures, and the recurrence of malignant and benign liver diseases, such as cholangiocarcinoma (CCA) and primary sclerosing cholangitis (PSC), are direct consequences linked to this inflammation. The accumulation of toxic metabolites, such as succinate, causes undirected electron flows, triggering the releases of reactive oxygen species (ROS) from a severely dysfunctional mitochondrial complex 1. This initiates the inflammatory IRI cascade, with subsequent ischemic biliary stricturing, and the upregulation of pro-tumorigenic signaling. Such inflammation is both local and systemic, promoting an immunocompromised status that can lead to the recurrence of underlying liver disease, both malignant and benign in nature. The traditional treatment for CCA was resection, when possible, followed by cytotoxic chemotherapy. Liver transplant oncology is increasingly recognized as a potentially curative approach for patients with intrahepatic (iCCA) and perihilar (pCCA) cholangiocarcinoma. The link between IRI and disease recurrence is increasingly recognized in transplant oncology for hepatocellular carcinoma. However, smaller numbers have prevented similar analyses for CCA. The mechanistic link may be even more critical in this disease, as IRI causes the most profound damage to the intrahepatic bile ducts. This article reviews the underlying mechanisms associated with biliary inflammation and biliary pathology after liver transplantation. One main focus is on the link between transplant-related IRI-associated inflammation and the recurrence of cholangiocarcinoma and benign liver diseases of the biliary tree. Risk factors and protective strategies are highlighted. Full article

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10 pages, 1412 KiB

Open AccessGuidelines

Postoperative Management of Portal Vein Arterialization: An Interdisciplinary Institutional Approach

by Ali Majlesara, Mohammad Golriz, Ali Ramouz, Elias Khajeh, Nastaran Sabetkish, Mark O. Wielpütz, Hugo Rio Tinto, Sepehr Abbasi Dezfouli, Martin Loos, Arianeb Mehrabi and De-Hua Chang

Cancers 2024, 16(13), 2459; https://doi.org/10.3390/cancers16132459 - 4 Jul 2024

Viewed by 966

Abstract

Portal vein arterialization (PVA) is a surgical procedure that plays a crucial role in hepatic vascular salvage when hepatic artery flow restoration remains elusive. Dedicated diagnostic vascular imaging and the timely management of PVA shunts are paramount to preventing complications, such as portal [...] Read more.

Portal vein arterialization (PVA) is a surgical procedure that plays a crucial role in hepatic vascular salvage when hepatic artery flow restoration remains elusive. Dedicated diagnostic vascular imaging and the timely management of PVA shunts are paramount to preventing complications, such as portal hypertension and thrombosis. Regrettably, a lack of standardized postoperative management protocols for PVA has increased morbidity and mortality rates post-procedure. In response to this challenge, we developed a PVA standard operating procedure (SOP) tailored to the needs of interventional radiologists. This SOP is designed to harmonize postoperative care, fostering scientific comparability across cases. This concise brief report aims to offer radiologists valuable insights into the PVA technique and considerations for post-PVA care and foster effective interdisciplinary collaboration. Full article

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10 pages, 1293 KiB

Open AccessArticle

Retrospective Long-Term Evaluation of Conventional Transarterial Chemoembolization for Hepatocellular Carcinoma over 20 Years

by Thomas J. Vogl, Hamzah Adwan, Leonard Wolff, Maximilian Lahrsow, Tatjana Gruber-Rouh, Nour-Eldin Abdelrehim Nour-Eldin, Jörg Trojan, Wolf-Otto Bechstein and Nagy N. N. Naguib

Cancers 2024, 16(8), 1498; https://doi.org/10.3390/cancers16081498 - 14 Apr 2024

Viewed by 1094

Abstract

The aim of this study was to retrospectively evaluate the effects of conventional transarterial chemoembolization (cTACE) for the treatment of hepatocellular carcinoma over 20 years regarding overall survival (OS) and prognostic factors for OS. During the period from 1996 to 2016, 836 patients [...] Read more.

The aim of this study was to retrospectively evaluate the effects of conventional transarterial chemoembolization (cTACE) for the treatment of hepatocellular carcinoma over 20 years regarding overall survival (OS) and prognostic factors for OS. During the period from 1996 to 2016, 836 patients with HCC were treated with cTACE. Data evaluation was performed on the basis of pre- and postinterventional MRI and CT scans. Survival analysis was performed by Kaplan–Meier estimator; prognostic factors were determined by the use of Cox regression analysis. Overall, 4084 (mean 4.89 TACE sessions/patient) procedures were assessed. Median OS was 700 days (99% CI, 632.8–767.2). Depending on the indication, patients treated with a neoadjuvant intention showed the best OS (1229 days, 99% CI 983.8–1474.2) followed by curative intention (787 days, 99% CI 696.3–877.7), and then palliative intention (360 days, 99% CI 328.4–391.6). Portal vein thrombosis (HR 2.19, CI 1.63–2.96, and p < 0.01) and Child–Pugh class B or worse (HR 1.44, CI 1.11–1.86, and p < 0.001) were significantly associated with shorter OS. Patients with HCC benefit from TACE after careful patient selection. Portal vein thrombosis and Child–Pugh class B or worse are significantly unfavorable prognostic factors for patients’ survival. Full article

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11 pages, 7225 KiB

Open AccessSystematic Review

The Impact of Radiofrequency Ablation on Survival Outcomes and Stent Patency in Patients with Unresectable Cholangiocarcinoma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

by Daniele Balducci, Michele Montori, Francesco Martini, Marco Valvano, Federico De Blasio, Maria Eva Argenziano, Giuseppe Tarantino, Antonio Benedetti, Emanuele Bendia, Marco Marzioni and Luca Maroni

Cancers 2024, 16(7), 1372; https://doi.org/10.3390/cancers16071372 - 30 Mar 2024

Cited by 1 | Viewed by 1292

Abstract

Endoluminal biliary radiofrequency ablation (RFA) has been proposed as a palliative treatment for patients with malignant biliary obstruction (MBO) in order to improve stent patency and survival. However, the existing data on patients with inoperable extrahepatic cholangiocarcinoma (eCCA) are conflicting. We performed a [...] Read more.

Endoluminal biliary radiofrequency ablation (RFA) has been proposed as a palliative treatment for patients with malignant biliary obstruction (MBO) in order to improve stent patency and survival. However, the existing data on patients with inoperable extrahepatic cholangiocarcinoma (eCCA) are conflicting. We performed a meta-analysis of randomized trials comparing RFA plus stenting versus stenting alone in patients with inoperable eCCA. We searched for trials published in the PubMed/MEDLINE, Scopus, and Cochrane databases up to November 2023. Data extraction was conducted from published studies, and a quality assessment was carried out in accordance with the guidelines recommended by the Cochrane Collaboration. Hazard ratios (HRs) with 95% CI were estimated from the trials. The primary endpoints of interest were overall survival and stent patency. Out of 275 results, 5 randomized trials and 370 patients were included. While overall survival was not different between the groups (HR 0.62; 95% CI 0.36–1.07; p = 0.09; I² = 80%;), the subgroup analysis of studies employing plastic stents showed a trend toward better survival in the RFA-treated group (HR 0.42; 95% CI 0.22–0.80; p = 0.009; I² = 72%). Stent patency was improved in patients receiving RFA (HR 0.64; 95% CI 0.45–0.90; p = 0.01; I² = 23%). Adverse events were not different between the groups (OR 1.21; 95% CI 0.69–2.12; p = 0.50; I² = 0%). Despite the promising results, high heterogeneity and potential biases in the included studies suggest the need for further high-quality randomized trials to explore the potential cumulative effects of RFA on CCA treatment outcomes. Full article

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15 pages, 3641 KiB

Open AccessArticle

Exploring the Genomic Landscape of Hepatobiliary Cancers to Establish a Novel Molecular Classification System

by Anthony J. Scholer, Rebecca K. Marcus, Mary Garland-Kledzik, Debopriya Ghosh, Miquel Ensenyat-Mendez, Joshua Germany, Juan A. Santamaria-Barria, Adam Khader, Javier I. J. Orozco and Melanie Goldfarb

Cancers 2024, 16(2), 325; https://doi.org/10.3390/cancers16020325 - 11 Jan 2024

Viewed by 1572

Abstract

Taxonomy of hepatobiliary cancer (HBC) categorizes tumors by location or histopathology (tissue of origin, TO). Tumors originating from different TOs can also be grouped by overlapping genomic alterations (GA) into molecular subtypes (MS). The aim of this study was to create novel HBC [...] Read more.

Taxonomy of hepatobiliary cancer (HBC) categorizes tumors by location or histopathology (tissue of origin, TO). Tumors originating from different TOs can also be grouped by overlapping genomic alterations (GA) into molecular subtypes (MS). The aim of this study was to create novel HBC MSs. Next-generation sequencing (NGS) data from the AACR-GENIE database were used to examine the genomic landscape of HBCs. Machine learning and gene enrichment analysis identified MSs and their oncogenomic pathways. Descriptive statistics were used to compare subtypes and their associations with clinical and molecular variables. Integrative analyses generated three MSs with different oncogenomic pathways independent of TO (n = 324; p < 0.05). HC-1 “hyper-mutated-proliferative state” MS had rapidly dividing cells susceptible to chemotherapy; HC-2 “adaptive stem cell-cellular senescence” MS had epigenomic alterations to evade immune system and treatment-resistant mechanisms; HC-3 “metabolic-stress pathway” MS had metabolic alterations. The discovery of HBC MSs is the initial step in cancer taxonomy evolution and the incorporation of genomic profiling into the TNM system. The goal is the development of a precision oncology machine learning algorithm to guide treatment planning and improve HBC outcomes. Future studies should validate findings of this study, incorporate clinical outcomes, and compare the MS classification to the AJCC 8th staging system. Full article

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2023

Jump to: 2024, 2022, 2021, 2020

14 pages, 570 KiB

Open AccessReview

Targetable Molecular Alterations in the Treatment of Biliary Tract Cancers: An Overview of the Available Treatments

by Marine Valery, Damien Vasseur, Francesco Fachinetti, Alice Boilève, Cristina Smolenschi, Anthony Tarabay, Leony Antoun, Audrey Perret, Alina Fuerea, Thomas Pudlarz, Valérie Boige, Antoine Hollebecque and Michel Ducreux

Cancers 2023, 15(18), 4446; https://doi.org/10.3390/cancers15184446 - 6 Sep 2023

Cited by 20 | Viewed by 2698

Abstract

Biliary tract cancers (BTCs) are rare tumours, most often diagnosed at an unresectable stage, associated with poor prognosis, with a 5-year survival rate not exceeding 10%. Only first- and second-line treatments are well codified with the combination of cisplatin-gemcitabine chemotherapy and immunotherapy followed [...] Read more.

Biliary tract cancers (BTCs) are rare tumours, most often diagnosed at an unresectable stage, associated with poor prognosis, with a 5-year survival rate not exceeding 10%. Only first- and second-line treatments are well codified with the combination of cisplatin-gemcitabine chemotherapy and immunotherapy followed by 5-FU and oxaliplatin chemotherapy, respectively. Many studies have shown that BTC, and more particularly intrahepatic cholangiocarcinoma (iCCA), have a high rate of targetable somatic alteration. To date, the FDA has approved several drugs. Ivosidenib targeting IDH1 mutations, as well as futibatinib and pemigatinib targeting FGFR2 fusions, are approved for pre-treated advanced CCA. The combination of dabrafenib and trametinib are approved for BRAFV600E mutated advanced tumours, NTRK inhibitors entrectinib and larotrectinib for tumours bearing NTRK fusion and prembrolizumab for MSI-H advanced tumours, involving a small percentage of BTC in these three settings. Several other potentially targetable alterations are found in BTC, such as HER2 mutations or amplifications or KRASG12C mutations and mutations in genes involved in DNA repair mechanisms. This review aims to clarify the specific diagnostic modalities for gene alterations and to summarize the results of the main trials and developments underway for the management of advanced BTC with targetable alterations. Full article

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11 pages, 2324 KiB

Open AccessArticle

A Real-World Comparative Analysis of Atezolizumab Plus Bevacizumab and Transarterial Chemoembolization Plus Radiotherapy in Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombosis

by Soon Kyu Lee, Jung Hyun Kwon, Sung Won Lee, Hae Lim Lee, Hee Yeon Kim, Chang Wook Kim, Do Seon Song, U Im Chang, Jin Mo Yang, Soon Woo Nam, Seok-Hwan Kim, Myeong Jun Song, Ji Hoon Kim, Ahlim Lee, Hyun Yang, Si Hyun Bae, Ji Won Han, Heechul Nam, Pil Soo Sung, Jeong Won Jang, Jong Young Choi, Seung Kew Yoon, Dong Jae Shim, Doyoung Kim and Myungsoo Kim Show full author list Hide full author list

Cancers 2023, 15(17), 4423; https://doi.org/10.3390/cancers15174423 - 4 Sep 2023

Cited by 5 | Viewed by 1982

Abstract

This study aimed to compare the treatment outcomes of atezolizumab-plus-bevacizumab (Ate/Bev) therapy with those of transarterial chemoembolization plus radiotherapy (TACE + RT) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) and without metastasis. Between June 2016 and October 2022, we [...] Read more.

This study aimed to compare the treatment outcomes of atezolizumab-plus-bevacizumab (Ate/Bev) therapy with those of transarterial chemoembolization plus radiotherapy (TACE + RT) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) and without metastasis. Between June 2016 and October 2022, we consecutively enrolled 855 HCC patients with PVTT. After excluding 758 patients, 97 patients (n = 37 in the Ate/Bev group; n = 60 in the TACE + RT group) were analyzed. The two groups showed no significant differences in baseline characteristics and had similar objective response and disease control rates. However, the Ate/Bev group showed a significantly higher one-year survival rate (p = 0.041) compared to the TACE + RT group, which was constantly displayed in patients with extensive HCC burden. Meanwhile, the clinical outcomes were comparable between the two groups in patients with unilobar intrahepatic HCC. In Cox-regression analysis, Ate/Bev treatment emerged as a significant factor for better one-year survival (p = 0.049). Finally, in propensity-score matching, the Ate/Bev group demonstrated a better one-year survival (p = 0.02) and PFS (p = 0.01) than the TACE + RT group. In conclusion, Ate/Bev treatment demonstrated superior clinical outcomes compared to TACE + RT treatment in HCC patients with PVTT. Meanwhile, in patients with unilobar intrahepatic HCC, TACE + RT could also be considered as an alternative treatment option alongside Ate/Bev therapy. Full article

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13 pages, 1454 KiB

Open AccessArticle

Low-Baseline PD1+ Granulocytes Predict Responses to Atezolizumab–Bevacizumab in Hepatocellular Carcinoma

by Catia Giovannini, Fabrizia Suzzi, Francesco Tovoli, Mariangela Bruccoleri, Mariarosaria Marseglia, Eleonora Alimenti, Francesca Fornari, Massimo Iavarone, Fabio Piscaglia and Laura Gramantieri

Cancers 2023, 15(6), 1661; https://doi.org/10.3390/cancers15061661 - 8 Mar 2023

Cited by 6 | Viewed by 1892

Abstract

Introduction: Immune check point inhibitors have recently entered the armamentarium of advanced hepatocellular carcinoma (HCC) treatment. Among them, the combination of atezolizumab plus bevacizumab has pushed it a step forward; however, a number of patients still present primary non-responses without any biomarker to [...] Read more.

Introduction: Immune check point inhibitors have recently entered the armamentarium of advanced hepatocellular carcinoma (HCC) treatment. Among them, the combination of atezolizumab plus bevacizumab has pushed it a step forward; however, a number of patients still present primary non-responses without any biomarker to predict responses to different options. Here, we aimed to identify a putative baseline biomarker to predict the response to atezolizumab–bevacizumab, by investigating whether baseline PD1+ and PD-L1+ peripheral granulocyte percentages might offer a non-invasive, cheap, and easily feasible assay. Methods: A prospective Italian cohort of 34 patients treated by atezolizumab–bevacizumab was tested to assay the baseline percentage of peripheral granulocytes and their PD1 and PD-L1 expression. The neutrophil to lymphocyte ratio (NLR) was also considered, and all data were compared with the clinical course of patients. Results: A low-baseline PD1+ peripheral granulocyte percentage turned out to predict responder patients (mean ±SD of PD1+ granulocyte percentage in responders versus non-responders: 9.9 ± 9.1 vs. 29.2 ± 17.6; student’s t-test, p < 0.01). In line, patients identified by a low PD1+ granulocyte percentage displayed a longer TTP (log-rank test, p < 0.0001). A lower granulocyte percentage on total white blood cells, irrespective of PD1 or PD-L1 expression, is also associated with responses to atezolizumab–bevacizumab (log-rank test, p < 0.05). No predictive value was observed for either the PD-L1+ granulocyte percentage or NLR. Conclusions: A low-baseline PD1+ peripheral granulocyte percentage is associated with responses to atezolizumab–bevacizumab treatment in advanced HCC. These findings encourage evaluating this minimally invasive, cheap, and easy test in further independent cohorts and outlining the relevance of innate immunity in the response to immune-checkpoint inhibitors. Full article

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12 pages, 737 KiB

Open AccessArticle

Role of Etiology in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Counterfactual Event-Based Mediation Analysis

by Rodolfo Sacco, Daryl Ramai, Raffaella Tortora, Giovan Giuseppe di Costanzo, Michela Emma Burlone, Mario Pirisi, Piera Federico, Bruno Daniele, Marianna Silletta, Paolo Gallo, Caterina Cocuzza, Maurizio Russello, Giuseppe Cabibbo, Gabriele Rancatore, Silvia Cesario, Gianluca Masi, Luca Marzi, Andrea Mega, Alessandro Granito, Giulia Pieri, Edoardo G. Giannini, Rosa Paolillo, Gennaro Gadaleta-Caldarola, Vincenzo Dadduzio, Guido Giordano, Luca Giacomelli, Simonetta Papa, Matteo Renzulli, Marcello Maida, Michele Ghidini, Mauro Borzio and Antonio Facciorusso Show full author list Hide full author list

Cancers 2023, 15(2), 381; https://doi.org/10.3390/cancers15020381 - 6 Jan 2023

Cited by 8 | Viewed by 2709

Abstract

Background: Whether the etiology of underlying liver disease represents a prognostic factor in patients with hepatocellular carcinoma (HCC) treated with lenvatinib is still a matter of debate. This study investigates whether the viral etiology of HCC plays a prognostic role in overall survival [...] Read more.

Background: Whether the etiology of underlying liver disease represents a prognostic factor in patients with hepatocellular carcinoma (HCC) treated with lenvatinib is still a matter of debate. This study investigates whether the viral etiology of HCC plays a prognostic role in overall survival (OS). Methods: Data derived from a multicenter series of 313 HCC patients treated with lenvatinib between 2019 and 2022 were analyzed. Actuarial survival estimates were computed using the Kaplan–Meier method and compared with the log-rank test. We performed an event-based counterfactual mediation analysis to estimate direct (chronic inflammation and immunosuppression), indirect (tobacco smoking, alcohol use, illicit drug abuse with injections), and the total effect of viral etiology on OS. Results were expressed as hazard ratio (HR) and 95% CI. Results: Median OS was 21 months (95% CI: 20–23) in the group with other etiologies and 15 months (14–16) in the group with viral etiology (p < 0.0001). The total effect of viral etiology was associated with OS (HR 2.76, 1.32–5.21), and it was mainly explained by the pure direct effect of viral etiology (HR 2.74, 1.15–4.45). By contrast, its total indirect effect was not associated with poorer survival (HR 1.05, 0.82–2.13). These results were confirmed when considering tobacco, alcohol consumption, or injection drug abuse as potential mediators. Median progression-free survival was 9 months (8–10) in patients with other etiologies and 6 months (5–7) in patients with viral etiology (p < 0.0001). No difference in terms of adverse event rate was observed between the two groups. Conclusions: Patients affected by HCC with nonviral etiology treated with lenvatinib exhibit longer survival than those with viral etiology. This finding may have relevance in the treatment decision-making process. Full article

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2022

Jump to: 2024, 2023, 2021, 2020

13 pages, 1123 KiB

Open AccessArticle

Preoperative Serum Markers and Risk Classification in Intrahepatic Cholangiocarcinoma: A Multicenter Retrospective Study

by Masaki Kaibori, Kengo Yoshii, Hisashi Kosaka, Masato Ota, Koji Komeda, Masaki Ueno, Daisuke Hokutou, Hiroya Iida, Kosuke Matsui and Mitsugu Sekimoto

Cancers 2022, 14(21), 5459; https://doi.org/10.3390/cancers14215459 - 7 Nov 2022

Cited by 3 | Viewed by 2044

Abstract

Accurate risk stratification selects patients who are expected to benefit most from surgery. This retrospective study enrolled 225 Japanese patients with intrahepatic cholangiocellular carcinoma (ICC) who underwent hepatectomy between January 2009 and December 2020 and identified preoperative blood test biomarkers to formulate a [...] Read more.

Accurate risk stratification selects patients who are expected to benefit most from surgery. This retrospective study enrolled 225 Japanese patients with intrahepatic cholangiocellular carcinoma (ICC) who underwent hepatectomy between January 2009 and December 2020 and identified preoperative blood test biomarkers to formulate a classification system that predicted prognosis. The optimal cut-off values of blood test parameters were determined by ROC curve analysis, with Cox univariate and multivariate analyses identifying prognostic factors. Risk classifications were established using classification and regression tree (CART) analysis. CART analysis revealed decision trees for recurrence-free survival (RFS) and overall survival (OS) and created three risk classifications based on machine learning of preoperative serum markers. Five-year rates differed significantly (p < 0.001) between groups: 60.4% (low-risk), 22.8% (moderate-risk), and 4.1% (high-risk) for RFS and 69.2% (low-risk), 32.3% (moderate-risk), and 9.2% (high-risk) for OS. No difference in OS was observed between patients in the low-risk group with or without postoperative adjuvant chemotherapy, although OS improved in the moderate group and was prolonged significantly in the high-risk group receiving chemotherapy. Stratification of patients with ICC who underwent hepatectomy into three risk groups for RFS and OS identified preoperative prognostic factors that predicted prognosis and were easy to understand and apply clinically. Full article

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12 pages, 679 KiB

Open AccessArticle

Modified Albumin-Bilirubin Grade and Alpha-Fetoprotein Score (mALF Score) for Predicting the Prognosis of Hepatocellular Carcinoma after Hepatectomy

by Masaki Kaibori, Kengo Yoshii, Kosuke Matsui, Hideyuki Matsushima, Hisashi Kosaka, Hidekazu Yamamoto, Kazunori Aoi, Takashi Yamaguchi, Katsunori Yoshida, Takeshi Hatanaka, Atsushi Hiraoka, Toshifumi Tada, Takashi Kumada and Mitsugu Sekimoto

Cancers 2022, 14(21), 5292; https://doi.org/10.3390/cancers14215292 - 27 Oct 2022

Cited by 4 | Viewed by 1923

Abstract

We developed and evaluated a modified albumin-bilirubin grade and α-fetoprotein (mALF) score, a nutritional and oncological assessment tool for patients with hepatocellular carcinoma (HCC) after surgical resection. Patients (n = 480) who underwent R0 resection between 2010 and 2020 were analyzed retrospectively. [...] Read more.

We developed and evaluated a modified albumin-bilirubin grade and α-fetoprotein (mALF) score, a nutritional and oncological assessment tool for patients with hepatocellular carcinoma (HCC) after surgical resection. Patients (n = 480) who underwent R0 resection between 2010 and 2020 were analyzed retrospectively. The mALF score assigned one point for a modified albumin-bilirubin (mALBI) grade 2b or 3 and one point for an α-fetoprotein (AFP) level ≥ 100 ng/mL. Patients were classified by mALF scores of 0 (mALBI grade 1/2a, AFP < 100 ng/mL), 1 (mALBI grade 2b/3 or AFP ≥ 100 ng/mL), or 2 (mALBI grade 2b/3, AFP ≥ 100 ng/mL) points. Liver reserve deteriorated and cancer progressed with increasing score. Postoperative complications (Clavien–Dindo classification ≥ 3) differed significantly among groups. The 5-year recurrence-free survival (RFS) rates were 34.8%, 11.2%, and 0.0% for 0, 1, and 2 points, respectively (1 or 2 versus 0 points, p < 0.001). The 5-year overall survival (OS) rates were 66.0%, 29.7%, and 17.8% for 0, 1, and 2 points, respectively (1 or 2 versus 0 points, p < 0.001). The mALF score was an independent prognostic predictor of RFS and OS. In HCC, the mALF score was effective for predicting postoperative complications and long-term survival. Full article

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13 pages, 831 KiB

Open AccessArticle

The Impact of KRAS Mutational Status on Long-Term Survival following Liver Resection for Hilar Cholangiocarcinoma

by Francesco Ardito, Francesco Razionale, Andrea Campisi, Angela Carlino, Maria Vellone, Simone Vani, Luigi M. Larocca and Felice Giuliante

Cancers 2022, 14(18), 4370; https://doi.org/10.3390/cancers14184370 - 8 Sep 2022

Cited by 2 | Viewed by 2479

Abstract

KRAS mutation is reportedly associated with poor prognosis in patients with different cancer types. However, mutational data on hilar cholangiocarcinoma are few and controversial. The aim of this study was to evaluate the rate of KRAS mutations in a single-center homogeneous population resected [...] Read more.

KRAS mutation is reportedly associated with poor prognosis in patients with different cancer types. However, mutational data on hilar cholangiocarcinoma are few and controversial. The aim of this study was to evaluate the rate of KRAS mutations in a single-center homogeneous population resected for hilar cholangiocarcinoma and the subsequent impact on prognosis. KRAS mutation status was evaluated in 54 patients undergoing major hepatectomy combined with resection of the main biliary confluence and regional lymphadenectomy for hilar cholangiocarcinoma between 2001 and 2019. Among these 54 patients, 12 (22.2%) had a KRAS mutation. KRAS mutation was not related with pathologic characteristics of the tumor. Five-year overall survival (OS) in patients with KRAS mutation was significantly lower than that observed in patients with KRAS wild type (0 vs. 49.2%, respectively; p = 0.003). In the multivariable analysis; independent predictors of poor OS were KRAS mutation (HR = 5.384; p = 0.003) and lymph node metastases (HR = 2.805; p = 0.023). The results of our study suggested that KRAS mutation in hilar cholangiocarcinoma was not rarely observed. KRAS mutation was an independent strong predictor of poor OS. KRAS mutation analysis should be included in the routine pathologic evaluation of resected hilar cholangiocarcinoma in order to better stratify prognosis Full article

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12 pages, 972 KiB

Open AccessArticle

Comparison of the New Neo-Glasgow Prognostic Score Based on the Albumin-Bilirubin Grade with Currently Used Nutritional Indices for Prognostic Prediction following Surgical Resection of Hepatocellular Carcinoma: A Multicenter Retrospective Study in Japan

by Masaki Kaibori, Atsushi Hiraoka, Hiroya Iida, Koji Komeda, Fumitoshi Hirokawa, Masaki Ueno, Hisashi Kosaka, Kosuke Matsui and Mitsugu Sekimoto

Cancers 2022, 14(9), 2091; https://doi.org/10.3390/cancers14092091 - 22 Apr 2022

Cited by 5 | Viewed by 1756

Abstract

Nutritional assessment is important for predicting a prognosis in hepatocellular carcinoma (HCC). The authors examined the utility of the recently developed neo-Glasgow prognostic score (GPS) as a nutritional prognostic assessment in HCC in a multicenter retrospective study of 271 patients with HCC and [...] Read more.

Nutritional assessment is important for predicting a prognosis in hepatocellular carcinoma (HCC). The authors examined the utility of the recently developed neo-Glasgow prognostic score (GPS) as a nutritional prognostic assessment in HCC in a multicenter retrospective study of 271 patients with HCC and Child-Pugh class A liver function who underwent R0 resection between 2011 and 2013. The median age was 72 years, 229 and 42 patients had Child-Pugh scores of 5 and 6, respectively, 223 patients had single tumors, the median tumor size was 3.6 cm, and open and laparoscopic resection were performed in 138 and 133 patients, respectively. We compared the prognostic predictive utility of the prognostic nutritional index, neutrophil/lymphocyte and platelet/lymphocyte ratios, controlling nutritional status score, GPS, and neo-GPS, which uses albumin-bilirubin grade (ALBI) instead of albumin. The c-indexes for the predictive prognostic value for overall survival (OS) and progression-free survival (PFS) were best for neo-GPS (OS: 0.571 vs. ≤0.555; PFS: 0.555 vs. ≤0.546). In multivariate analysis with the Cox proportional hazards model, elevated alpha-fetoprotein (AFP; ≥100 ng/mL; hazard ratio [HR] 2.190, 95% confidence interval [CI] 1.493–3.211, p < 0.001), multiple tumors (HR 1.784, 95%CI 1.178–2.703, p = 0.006), tumor size of ≥5 cm (HR 1.508, 95%CI 1.037–2.193, p = 0.032), and neo-GPS of ≥1 (HR 1.554, 95%CI 1.074–2.247, p = 0.019) were significant prognostic factors for OS, whereas elevated AFP (≥100 ng/mL) (HR 1.743, 95%CI 1.325–2.292, p < 0.001), multiple tumors (HR 1.537, 95%CI 1.148–2.057, p = 0.004), and neo-GPS of ≥1 (HR 1.522, 95%CI 1.186–1.954, p = 0.001) were significant prognostic factors for PFS. A neo-GPS of ≥1 was associated with a higher rate of high-grade (≥3) Clavien-Dindo complications than a neo-GPS of <1 (31.1% vs. 17.0%, p = 0.007). Neo-GPS was a good prognostic nutritional assessment tool for the prediction of postoperative complications and prognosis in patients undergoing surgical HCC resection. Full article

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11 pages, 650 KiB

Open AccessArticle

Modified FOLFIRINOX as a Second-Line Treatment for Patients with Gemcitabine-Failed Advanced Biliary Tract Cancer: A Prospective Multicenter Phase II Study

by Yong-Pyo Lee, Sung Yong Oh, Kwang Min Kim, Se-Il Go, Jung Hoon Kim, Seok Jae Huh, Jung Hun Kang and Jun Ho Ji

Cancers 2022, 14(8), 1950; https://doi.org/10.3390/cancers14081950 - 13 Apr 2022

Cited by 4 | Viewed by 2225

Abstract

Background: After the publication of the ABC-02 trial, gemcitabine and cisplatin combination therapy (GP) became the standard first-line treatment for advanced biliary tract cancer (BTC). Despite GP therapy, most patients suffer from disease progression. The ABC-06 trial recommended FOLFOX as a second-line treatment, [...] Read more.

Background: After the publication of the ABC-02 trial, gemcitabine and cisplatin combination therapy (GP) became the standard first-line treatment for advanced biliary tract cancer (BTC). Despite GP therapy, most patients suffer from disease progression. The ABC-06 trial recommended FOLFOX as a second-line treatment, but its efficacy was modest. In this phase II study, we looked at the efficacy and safety of a second-line modified dose of FOLFIRINOX (mFOLFIRINOX) for patients who had failed first-line gemcitabine-based treatment. Methods: From January 2020 to January 2021, 34 patients with advanced BTC who failed first-line gemcitabine-based chemotherapy were enrolled. We evaluated the clinical efficacy and safety outcomes of mFOLFIRINOX. Results: With a median follow-up duration of 13.4 months, the median progression-free survival and overall survival was 2.8 months (95% confidence interval (CI): 1.6–4.0 months) and 6.2 months (95% CI: 5.0–7.4 months), respectively. The objective response rate was 14.7% with no complete response. The disease control rate was 61.7%, with a disease control duration of 4.2 months. Due to the rapid progression of the disease, approximately half of all patients received less than three cycles of treatment. The most common type of adverse event (AEs) was hematopoietic AEs. The incidence of non-hematopoietic AEs was relatively low. Conclusions: The efficacy of mFOLFIRINOX as a second-line treatment in advanced BTC patients after the failure of gemcitabine-based first-line treatment was replicated, albeit with slightly shorter survival results compared to previous studies. Long-term administration of mFOLFIRINOX with toxicity management might offer a survival benefit. Full article

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19 pages, 909 KiB

Open AccessReview

Targeted Therapies for Perihilar Cholangiocarcinoma

by Simon Gray, Angela Lamarca, Julien Edeline, Heinz-Josef Klümpen, Richard A. Hubner, Mairéad G. McNamara and Juan W. Valle

Cancers 2022, 14(7), 1789; https://doi.org/10.3390/cancers14071789 - 31 Mar 2022

Cited by 7 | Viewed by 3156

Abstract

Perihilar cholangiocarcinoma (pCCA) is the anatomical sub-group of biliary tract cancer (BTC) arising between the second-order intrahepatic bile ducts and the cystic duct. Together with distal and intrahepatic cholangiocarcinoma (dCCA and iCCA; originating distal to, and proximal to this, respectively), gallbladder cancer (GBC) [...] Read more.

Perihilar cholangiocarcinoma (pCCA) is the anatomical sub-group of biliary tract cancer (BTC) arising between the second-order intrahepatic bile ducts and the cystic duct. Together with distal and intrahepatic cholangiocarcinoma (dCCA and iCCA; originating distal to, and proximal to this, respectively), gallbladder cancer (GBC) and ampulla of Vater carcinoma (AVC), these clinicopathologically and molecularly distinct entities comprise biliary tract cancer (BTC). Most pCCAs are unresectable at diagnosis, and for those with resectable disease, surgery is extensive, and recurrence is common. Therefore, the majority of patients with pCCA will require systemic treatment for advanced disease. The prognosis with cytotoxic chemotherapy remains poor, driving interest in therapies targeted to the molecular nature of a given patient’s cancer. In recent years, the search for efficacious targeted therapies has been fuelled both by whole-genome and epigenomic studies, looking to uncover the molecular landscape of CCA, and by specifically testing for aberrations where established therapies exist in other indications. This review aims to provide a focus on the current molecular characterisation of pCCA, targeted therapies applicable to pCCA, and future directions in applying personalised medicine to this difficult-to-treat malignancy. Full article

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11 pages, 5890 KiB

Open AccessArticle

Predicting Complications following Surgical Resection of Hepatocellular Carcinoma Using Newly Developed Neo-Glasgow Prognostic Score with ALBI Grade: Comparison of Open and Laparoscopic Surgery Cases

by Masaki Kaibori, Atsushi Hiraoka, Kosuke Matsui, Hideyuki Matsushima, Hisashi Kosaka, Hidekazu Yamamoto, Takashi Yamaguchi, Katsunori Yoshida and Mitsugu Sekimoto

Cancers 2022, 14(6), 1402; https://doi.org/10.3390/cancers14061402 - 9 Mar 2022

Cited by 10 | Viewed by 2034

Abstract

Background/Aim: Nutritional assessment is known to be important for predicting prognosis in patients with malignant diseases. This study examined the usefulness of a prognostic predictive nutritional assessment tool for hepatocellular carcinoma (HCC) patients treated with surgical resection. Materials/Methods: HCC patients (n = [...] Read more.

Background/Aim: Nutritional assessment is known to be important for predicting prognosis in patients with malignant diseases. This study examined the usefulness of a prognostic predictive nutritional assessment tool for hepatocellular carcinoma (HCC) patients treated with surgical resection. Materials/Methods: HCC patients (n = 429) classified as Child–Pugh A who underwent an R0 resection between 2010 and 2020 were retrospectively analyzed (median age 73 years, males 326 (76.0%), Child–Pugh score 5:6 = 326:103, single tumor 340 (79.2%), median tumor size 3.5 cm, open:laparoscopic = 304:125). Glasgow prognostic score (GPS) and the newly developed neo-GPS method, which uses albumin–bilirubin grade 1 instead of albumin, were evaluated to compare their usefulness for prognosis prediction. Results: Median survival time for patients with a GPS score of 0, 1, and 2 was 120, 51, and 20 months, respectively. As for neo-GPS, that for those with a score of 0, 1, and 2 was not applicable (NA), 53 months, and 35 months, respectively (each p < 0.001; c-index: 0.556 and 0.611, respectively). Furthermore, median progression-free survival was 33, 22, and 9 months, and 41, 24, and 15 months, respectively (each p < 0.001; c-index: 0.539 and 0.578, respectively). As compared to patients with a high GPS (≥1), those with a high neo-GPS (≥1) showed a greater rate of high Clavien–Dindo classification (≥3) (39.2% vs. 65.1%). A comparison of patients with a high GPS (≥1) with those with a high neo-GPS (≥1) showed no significant difference regarding frequency of open or laparoscopic hepatectomy (17.4% vs. 15.2%, p = 0.670; 44.7% vs. 43.2%, p = 0.831, respectively), while the frequency of high Clavien–Dindo classification (≥3) was lower in patients who underwent a laparoscopic hepatectomy (11.2% vs. 22.7%, p = 0.007). Conclusion: The present findings suggest that the newly developed neo-GPS based on ALBI grade is an effective prognostic nutritional assessment tool and can be used for prediction of postoperative complications. Full article

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12 pages, 2661 KiB

Open AccessArticle

Impact of Exogenous Treatment with Histidine on Hepatocellular Carcinoma Cells

by Yusun Park, Yeonju Han, Dongwoo Kim, Sua Cho, WonJin Kim, Hyemin Hwang, Hye Won Lee, Dai Hoon Han, Kyung Sik Kim, Mijin Yun and Misu Lee

Cancers 2022, 14(5), 1205; https://doi.org/10.3390/cancers14051205 - 25 Feb 2022

Cited by 6 | Viewed by 2899

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib, a multi-kinase inhibitor, is the first-line therapy for advanced HCC. However, long-term exposure to sorafenib often results in reduced sensitivity and the development of resistance. Although various amino acids [...] Read more.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib, a multi-kinase inhibitor, is the first-line therapy for advanced HCC. However, long-term exposure to sorafenib often results in reduced sensitivity and the development of resistance. Although various amino acids have been shown to contribute to cancer initiation and progression, little is known about the effects of histidine, a dietary essential amino acid that is partially taken up via histidine/large neutral amino acid transporter (LAT1), on cancer cells. In this study, we evaluated the effects of histidine on HCC cells and sensitivity to sorafenib. Remarkably, we found that exogenous histidine treatment induced a reduction in the expression of tumor markers related to glycolysis (GLUT1 and HK2), inflammation (STAT3), angiogenesis (VEGFB and VEGFC), and stem cells (CD133). In addition, LAT1 expression was downregulated in HCC tumor regions with high expression of GLUT1, CD133, and pSTAT3, which are known to induce sorafenib resistance. Finally, we demonstrated that combined treatment with sorafenib and histidine could be a novel therapeutic strategy to enhance the sensitivity to sorafenib, thereby improving long-term survival in HCC. Full article

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11 pages, 1331 KiB

Open AccessArticle

The Impact of a Preoperative Staging System on Accurate Prediction of Prognosis in Intrahepatic Cholangiocarcinoma

by Hisashi Kosaka, Masaki Ueno, Koji Komeda, Daisuke Hokuto, Hiroya Iida, Fumitoshi Hirokawa, Kosuke Matsui, Mitsugu Sekimoto and Masaki Kaibori

Cancers 2022, 14(5), 1107; https://doi.org/10.3390/cancers14051107 - 22 Feb 2022

Cited by 7 | Viewed by 1873

Abstract

Background: Non-invasive biomarkers detected preoperatively are still inadequate for treatment decision making for patients with intrahepatic cholangiocarcinoma (ICC). In this study, we analyzed preoperative findings to establish a novel preoperative staging system (PRE-Stage) for patients with ICC. Methods: The clinical data of 227 [...] Read more.

Background: Non-invasive biomarkers detected preoperatively are still inadequate for treatment decision making for patients with intrahepatic cholangiocarcinoma (ICC). In this study, we analyzed preoperative findings to establish a novel preoperative staging system (PRE-Stage) for patients with ICC. Methods: The clinical data of 227 consecutive patients with histologically confirmed ICC following hepatectomy at five university hospitals were analyzed. Results: Cox proportional hazards regression analysis of survival revealed that a CRP–albumin–lymphocyte index < 3, central tumor location, and CA19-9 level > 40 U/mL were prognostic factors among the preoperatively obtained clinical findings (hazard ratios (HRs) of all three factors for disease-specific survival (DSS) and disease-free survival (DFS: 2.4–3.3 and 1.7–2.9; all p < 0.05). The PRE-Stage was developed using these three prognostic factors, and it was able to significantly predict DSS and DFS when the patients were stratified into four stages (p < 0.05). In addition, the PRE-Stage resulted in similar HRs as those of the Liver Cancer Study Group of Japan (LCSGJ) stage (HRs for DSS: PRE-Stage, 1.985; LCSGJ stage, 1.923; HRs for DFS: LCSGJ stage, 1.909, and PRE-Stage, 1.623, all p < 0.05). Conclusion: The PRE-Stage demonstrated similar accuracy in predicting the prognosis of ICC as that of the LCSGJ stage, which is based on postoperative findings. The PRE-Stage may contribute to appropriate treatment decision making. Full article

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16 pages, 2498 KiB

Open AccessArticle

Transarterial Radioembolization for Unresectable Hepatocellular Carcinoma: Real-Life Efficacy and Safety Analysis of Korean Patients

by Sun Young Yim, Ho Soo Chun, Jae Seung Lee, Ji-Hwan Lim, Tae Hyung Kim, Beom Kyung Kim, Seung Up Kim, Jun Yong Park, Sang Hoon Ahn, Gyoung Min Kim, Jong Yun Won, Yeon Seok Seo, Yun Hwan Kim, Soon Ho Um and Do Young Kim

Cancers 2022, 14(2), 385; https://doi.org/10.3390/cancers14020385 - 13 Jan 2022

Cited by 8 | Viewed by 2431

Abstract

Transarterial radioembolization (TARE) has become widely used in the treatment of HCC, one of the most common causes of cancer mortality worldwide. Here we investigated the long-term clinical outcomes of patients with hepatocellular carcinoma (HCC) treated with TARE in a multi-medical center in [...] Read more.

Transarterial radioembolization (TARE) has become widely used in the treatment of HCC, one of the most common causes of cancer mortality worldwide. Here we investigated the long-term clinical outcomes of patients with hepatocellular carcinoma (HCC) treated with TARE in a multi-medical center in Korea. A total of 149 patients treated with TARE from 2008–2014 were recruited. The pre-treatment HCC stage was classified according to the BCLC stage, of which C and D were defined as advanced HCC. Advanced HCC stage and Child–Turcotte–Pugh (CTP) score A were identified in 62 (42%) and 134 (90%) patients, respectively. Portal vein thrombosis (PVT) was identified in 58 patients (38.9%). The median time to progression (TTP) was 14 months, and the median overall survival (OS) and progression-free survival (PFS) were 18.6 and 8.9 months, respectively. The overall tumor response was 47%, and the disease control rate was 78%. OS and PFS differed significantly according to the presence of liver cirrhosis, extrahepatic metastasis, tumor response and curative treatment after TARE (all, p < 0.05). Multiple tumors and major PVT were other independent factors related to OS, while the des-gamma carboxy protein level predicted PFS (all, p < 0.05). Tumor size was an independent predictor of tumor response. TTP, OS and PFS all differed among BCLC stages. The serious adverse effect after TARE was clinically not significant. Therefore, TARE is safe and effective in treating early to advanced HCCs. Full article

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2021

Jump to: 2024, 2023, 2022, 2020

11 pages, 962 KiB

Open AccessArticle

Beneficial Prognostic Effects of Aspirin in Patients Receiving Sorafenib for Hepatocellular Carcinoma: A Tale of Multiple Confounders

by Luca Ielasi, Francesco Tovoli, Matteo Tonnini, Raffaella Tortora, Giulia Magini, Rodolfo Sacco, Tiziana Pressiani, Franco Trevisani, Vito Sansone, Giovanni Marasco, Fabio Piscaglia and Alessandro Granito

Cancers 2021, 13(24), 6376; https://doi.org/10.3390/cancers13246376 - 20 Dec 2021

Cited by 14 | Viewed by 3052

Abstract

Case–control observational studies suggested that aspirin might prevent hepatocellular carcinoma (HCC) in high-risk patients, even if randomized clinical trials are lacking. Information regarding aspirin in subjects who already developed HCC, especially in its advanced stage, are scarce. While aspirin might be a low-cost [...] Read more.

Case–control observational studies suggested that aspirin might prevent hepatocellular carcinoma (HCC) in high-risk patients, even if randomized clinical trials are lacking. Information regarding aspirin in subjects who already developed HCC, especially in its advanced stage, are scarce. While aspirin might be a low-cost option to improve the prognosis, multiple confounders and safety concerns are to be considered. In our retrospective analyses of a prospective dataset (n = 699), after assessing the factors associated with aspirin prescription, we applied an inverse probability treatment weight analysis to address the prescription bias. Analyses of post-sorafenib survival were also performed to reduce the influence of subsequent medications. Among the study population, 133 (19%) patients were receiving aspirin at the time of sorafenib prescription. Aspirin users had a higher platelet count and a lower prevalence of esophageal varices, macrovascular invasion, and Child–Pugh B status. The benefit of aspirin was confirmed in terms of overall survival (HR 0.702, 95% CI 0.543–0.908), progression-free survival, disease control rate (58.6 vs. 49.5%, p < 0.001), and post-sorafenib survival even after weighting. Minor bleeding events were more frequent in the aspirin group. Aspirin use was associated with better outcomes, even after the correction for confounders. While safety concerns arguably remain a problem, prospective trials for patients at low risk of bleeding are warranted. Full article

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12 pages, 797 KiB

Open AccessArticle

Pre-Transplant Alpha-Fetoprotein > 25.5 and Its Dynamic on Waitlist Are Predictors of HCC Recurrence after Liver Transplantation for Patients Meeting Milan Criteria

by Bianca Magro, Domenico Pinelli, Massimo De Giorgio, Maria Grazia Lucà, Arianna Ghirardi, Alessandra Carrobio, Giuseppe Baronio, Luca Del Prete, Franck Nounamo, Andrea Gianatti, Michele Colledan and Stefano Fagiuoli

Cancers 2021, 13(23), 5976; https://doi.org/10.3390/cancers13235976 - 27 Nov 2021

Cited by 6 | Viewed by 1810

Abstract

Background and Aim: Hepatocellular carcinoma (HCC) recurrence rates after liver transplantation (LT) range between 8 and 20%. Alpha-fetoprotein (AFP) levels at transplant can predict HCC recurrence, however a defined cut-off value is needed to better stratify patients. The aim of this study was [...] Read more.

Background and Aim: Hepatocellular carcinoma (HCC) recurrence rates after liver transplantation (LT) range between 8 and 20%. Alpha-fetoprotein (AFP) levels at transplant can predict HCC recurrence, however a defined cut-off value is needed to better stratify patients. The aim of this study was to evaluate the rate of HCC recurrence at our centre and to identify predictors, focusing on AFP. Methods: We retrospectively analysed 236 consecutive patients that were waitlisted for HCC who all met the Milan criteria from January 2001 to December 2017 at our liver transplant centre. A total of twenty-nine patients dropped out while they were waitlisted, and 207 patients were included in the final analysis. All survival analyses included the competing-risk model. Results: The mean age was 56.8 ± 6.8 years. A total of 14% were female (n = 29/207). The median MELD (model for end-stage liver disease) at LT was 12 (9–16). The median time on the waitlist was 92 (41–170) days. The HCC recurrence rate was 16.4% (n = 34/208). The mean time to recurrence was 3.3 ± 2.8 years. The median AFP levels at transplant were higher in patients with HCC recurrence (p < 0.001). At multivariate analysis, the AFP value at transplant that was greater than 25.5 ng/mL (AUC 0.69) was a strong predictor of HCC recurrence after LT [sHR 3.3 (1.6–6.81); p = 0.001]. The HCC cumulative incidence function (CIF) of recurrence at 10 years from LT was significantly higher in patients with AFP > 25.5 ng/mL [34.3% vs. 11.5% (p = 0.001)]. Moreover, an increase in AFP > 20.8%, was significantly associated with HCC recurrence (p = 0.034). Conclusions: In conclusion, in our retrospective study, the AFP level at transplant > 25.5 ng/mL and its increase greater than 20.8% on the waitlist were strong predictors of HCC recurrence after LT in a cohort of patients that were waitlisted within the Milan criteria. However further studies are needed to validate these data. Full article

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24 pages, 13455 KiB

Open AccessReview

Interventional Radiology Image-Guided Locoregional Therapies (LRTs) and Immunotherapy for the Treatment of HCC

by Pierpaolo Biondetti, Lorenzo Saggiante, Anna Maria Ierardi, Massimo Iavarone, Angelo Sangiovanni, Filippo Pesapane, Enrico Maria Fumarola, Pietro Lampertico and Gianpaolo Carrafiello

Cancers 2021, 13(22), 5797; https://doi.org/10.3390/cancers13225797 - 18 Nov 2021

Cited by 15 | Viewed by 3864

Abstract

Image-guided locoregional therapies (LRTs) are a crucial asset in the treatment of hepatocellular carcinoma (HCC), which has proven to be characterized by an impaired antitumor immune status. LRTs not only directly destroy tumor cells but also have an immunomodulating role, altering the tumor [...] Read more.

Image-guided locoregional therapies (LRTs) are a crucial asset in the treatment of hepatocellular carcinoma (HCC), which has proven to be characterized by an impaired antitumor immune status. LRTs not only directly destroy tumor cells but also have an immunomodulating role, altering the tumor microenvironment with potential systemic effects. Nevertheless, the immune activation against HCC induced by LRTs is not strong enough on its own to generate a systemic significant antitumor response, and it is incapable of preventing tumor recurrence. Currently, there is great interest in the possibility of combining LRTs with immunotherapy for HCC, as this combination may result in a mutually beneficial and synergistic relationship. On the one hand, immunotherapy could amplify and prolong the antitumoral immune response of LRTs, reducing recurrence cases and improving outcome. On the other hand, LTRs counteract the typical immunosuppressive HCC microenvironment and status and could therefore enhance the efficacy of immunotherapy. Here, after reviewing the current therapeutic options for HCC, we focus on LRTs, describing for each of them the technique and data on its effect on the immune system. Then, we describe the current status of immunotherapy and finally report the recently published and ongoing clinical studies testing this combination. Full article

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17 pages, 4416 KiB

Open AccessReview

Locoregional Treatments for Bridging and Downstaging HCC to Liver Transplantation

by Laura Crocetti, Elena Bozzi, Paola Scalise, Irene Bargellini, Giulia Lorenzoni, Davide Ghinolfi, Daniela Campani, Emanuele Balzano, Paolo De Simone and Roberto Cioni

Cancers 2021, 13(21), 5558; https://doi.org/10.3390/cancers13215558 - 5 Nov 2021

Cited by 27 | Viewed by 2966

Abstract

Liver transplantation (LT) is the first-line treatment for patients diagnosed with unresectable early-stage hepatocellular carcinoma (HCC) in the setting of cirrhosis. It is well known that HCC patients within the Milan criteria (solitary tumour ≤ 5 cm or ≤3 tumours, each <3 cm) [...] Read more.

Liver transplantation (LT) is the first-line treatment for patients diagnosed with unresectable early-stage hepatocellular carcinoma (HCC) in the setting of cirrhosis. It is well known that HCC patients within the Milan criteria (solitary tumour ≤ 5 cm or ≤3 tumours, each <3 cm) could undergo LT with excellent results. However, there is a growing tendency to enlarge inclusion criteria since the Milan criteria are nowadays considered too restrictive and may exclude patients who would benefit from LT. On the other hand, there is a persistent shortage of donor organs. In this scenario, there is consensus about the role of loco-regional therapy (LRT) during the waiting list to select patients who would benefit more from LT, reducing the risk of drop off from the waiting list as well as decreasing tumour dimension to meet acceptable criteria for LT. In this review, current evidence on the safety, efficacy and utility of LRTs as neoadjuvant therapies before LT are summarized. Full article

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16 pages, 1176 KiB

Open AccessArticle

Image-Guided Liver Stereotactic Body Radiotherapy Using VMAT and Real-Time Adaptive Tumor Gating: Evaluation of the Efficacy and Toxicity for Hepatocellular Carcinoma

by Marie Cantaloube, Florence Castan, Morgane Creoff, Jessica Prunaretty, Karl Bordeau, Morgan Michalet, Eric Assenat, Boris Guiu, Georges-Philippe Pageaux, Marc Ychou, Norbert Aillères, Pascal Fenoglietto, David Azria and Olivier Riou

Cancers 2021, 13(19), 4853; https://doi.org/10.3390/cancers13194853 - 28 Sep 2021

Cited by 5 | Viewed by 2377

Abstract

Liver SBRT is a therapeutic option for the treatment of HCC in patients not eligible for other local therapies. We retrospectively report the outcomes of a cohort of consecutive patients treated with SBRT for HCC at the Montpellier Cancer Institute. Between March 2013 [...] Read more.

Liver SBRT is a therapeutic option for the treatment of HCC in patients not eligible for other local therapies. We retrospectively report the outcomes of a cohort of consecutive patients treated with SBRT for HCC at the Montpellier Cancer Institute. Between March 2013 and December 2018, 66 patients were treated with image-guided liver SBRT using VMAT and real-time adaptive tumor gating in our institute. The main endpoints considered in this study were local control, disease-free survival, overall survival, and toxicity. The median follow-up was 16.8 months. About 66.7% had prior liver treatment. Most patients received 50 Gy in five fractions of 10 Gy. No patient had local recurrence. Overall survival and disease-free survival were, respectively, 83.9% and 46.7% at one year. In multivariate analysis, the diameter of the lesions was a significant prognostic factor associated with disease-free survival (HR = 2.57 (1.19–5.53) p = 0.02). Regarding overall survival, the volume of PTV was associated with lower overall survival (HR = 2.84 (1.14–7.08) p = 0.025). No grade 3 toxicity was observed. One patient developed a grade 4 gastric ulcer, despite the dose constraints being respected. Image-guided liver SBRT with VMAT is an effective and safe treatment in patients with inoperable HCC, even in heavily pre-treated patients. Further prospective evaluation will help to clarify the role of SBRT in the management of HCC patients. Full article

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10 pages, 668 KiB

Open AccessArticle

Microwave Ablation of Very-Early- and Early-Stage HCC: Efficacy Evaluation by Correlation with Histology after Liver Transplantation

by Laura Crocetti, Paola Scalise, Elena Bozzi, Daniela Campani, Piercarlo Rossi, Rosa Cervelli, Irene Bargellini, Davide Ghinolfi, Paolo De Simone and Roberto Cioni

Cancers 2021, 13(14), 3420; https://doi.org/10.3390/cancers13143420 - 8 Jul 2021

Cited by 8 | Viewed by 2113

Abstract

Microwave (MW) ablation is a worldwide-diffused technique for the percutaneous ablation of hepatocellular carcinoma (HCC). Nevertheless, the efficacy of this technique still needs to be confirmed in pathological specimens. The purpose of this study was to evaluate the efficacy of MW ablation by [...] Read more.

Microwave (MW) ablation is a worldwide-diffused technique for the percutaneous ablation of hepatocellular carcinoma (HCC). Nevertheless, the efficacy of this technique still needs to be confirmed in pathological specimens. The purpose of this study was to evaluate the efficacy of MW ablation by correlation with histology in excised liver samples at the time of liver transplantation (LT). All patients with MW-ablated HCC who subsequently underwent LT between 2012 and 2020 were retrospectively evaluated. In the explanted livers, the treated lesions were evaluated at pathology, and the necrosis was classified as complete or partial. Thirty-six HCCs were ablated in 30 patients (20.9 ± 6.1 mm, a range of 10–30 mm). Ablations were performed with a single insertion of a MW antenna under ultrasound or CT guidance. A complete radiological response was demonstrated in 30/36 nodules (83.3%) in 24/30 patients (80%) at imaging performed one-month after MW ablation. At pathology, of the 36 treated nodules, 28 (77.8%) showed a complete necrosis, and 8 (22.2%) showed a pathological partial necrosis. Good agreement was found between the imaging performed one-month after treatment and the complete pathological response (Cohen’s k = 0.65). The imaging accuracy in detecting a complete response to treatment was 88.9%. All lesions with complete necrosis did not show recurrence at follow-up imaging until transplantation. The rad-path correlation in the explanted livers showed that MW ablation achieved a high rate of complete necrosis if a macroscopical complete ablation was obtained. Full article

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12 pages, 883 KiB

Open AccessArticle

The Impact of Time Interval between Hepatic Resection and Liver Transplantation on Clinical Outcome in Patients with Hepatocellular Carcinoma

by Matteo Serenari, Enrico Prosperi, Marc-Antoine Allard, Michele Paterno, Nicolas Golse, Andrea Laurenzi, René Adam, Matteo Ravaioli, Daniel Cherqui and Matteo Cescon

Cancers 2021, 13(10), 2398; https://doi.org/10.3390/cancers13102398 - 15 May 2021

Cited by 4 | Viewed by 1606

Abstract

Hepatic resection (HR) for hepatocellular carcinoma (HCC) may require secondary liver transplantation (SLT). However, a previous HR is supposed to worsen post-SLT outcomes. Data of patients treated by SLT between 2000 and 2018 at two tertiary referral centers were analyzed. The primary outcome [...] Read more.

Hepatic resection (HR) for hepatocellular carcinoma (HCC) may require secondary liver transplantation (SLT). However, a previous HR is supposed to worsen post-SLT outcomes. Data of patients treated by SLT between 2000 and 2018 at two tertiary referral centers were analyzed. The primary outcome of the study was to analyze the impact of HR on post-LT complications. A Comprehensive Complication Index ≥ 29.6 was chosen as cutoff. The secondary outcome was HCC-related death by means of competing-risk regression analysis. In the study period, 140 patients were included. Patients were transplanted in a median of 23 months after HR (IQR 14–41). Among all the features analyzed regarding the prior HR, only time interval between HR and SLT (time HR-SLT) was an independent predictor of severe complications after LT (OR = 0.98, p < 0.001). According to fractional polynomial regression, the probability of severe complications increased up to 15 months after HR (43%), then slowly decreased over time (OR = 0.88, p < 0.001). There was no significant association between HCC-related death and time HR-SLT at the multivariable competing risks regression model (SHR, 1.06; 95% CI: 0.69–1.62, p = 0.796). This study showed that time HR-SLT was key in predicting complications after LT, without affecting HCC-related death. Full article

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12 pages, 533 KiB

Open AccessReview

Human Endogenous Retrovirus Reactivation: Implications for Cancer Immunotherapy

by Annacarmen Petrizzo, Concetta Ragone, Beatrice Cavalluzzo, Angela Mauriello, Carmen Manolio, Maria Tagliamonte and Luigi Buonaguro

Cancers 2021, 13(9), 1999; https://doi.org/10.3390/cancers13091999 - 21 Apr 2021

Cited by 21 | Viewed by 5823

Abstract

Human endogenous retroviruses (HERVs) derive from ancestral exogenous retroviruses whose genetic material has been integrated in our germline DNA. Several lines of evidence indicate that cancer immunotherapy may benefit from HERV reactivation, which can be induced either by drugs or by cellular changes [...] Read more.

Human endogenous retroviruses (HERVs) derive from ancestral exogenous retroviruses whose genetic material has been integrated in our germline DNA. Several lines of evidence indicate that cancer immunotherapy may benefit from HERV reactivation, which can be induced either by drugs or by cellular changes occurring in tumor cells. Indeed, several studies indicate that HERV proviral DNA can be transcribed either to double-stranded RNA (dsRNA) that is sensed as a “danger signal” by pattern recognition receptors (PRRs), leading to a viral mimicry state, or to mRNA that is translated into proteins that may contribute to the landscape of tumor-specific antigens (TSAs). Alternatively, HERV reactivation is associated with the expression of long noncoding RNAs (lncRNAs). In this review, we will highlight recent findings on HERV reactivation in cancer and its implications for cancer immunotherapy. Full article

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13 pages, 1134 KiB

Open AccessArticle

Surgical Resection vs. Percutaneous Ablation for Single Hepatocellular Carcinoma: Exploring the Impact of Li-RADS Classification on Oncological Outcomes

by Leonardo Centonze, Stefano Di Sandro, Andrea Lauterio, Riccardo De Carlis, Samuele Frassoni, Antonio Rampoldi, Bruno Tuscano, Vincenzo Bagnardi, Angelo Vanzulli and Luciano De Carlis

Cancers 2021, 13(7), 1671; https://doi.org/10.3390/cancers13071671 - 1 Apr 2021

Cited by 19 | Viewed by 2739

Abstract

Background: Single hepatocellular carcinoma (HCC) benefits from surgical resection (SR) or US-guided percutaneous ablation (PA), although the best approach is still debated. We evaluated the impact of Li-RADS classification on the oncological outcomes of SR vs. PA as single HCC first-line treatment. [...] Read more.

Background: Single hepatocellular carcinoma (HCC) benefits from surgical resection (SR) or US-guided percutaneous ablation (PA), although the best approach is still debated. We evaluated the impact of Li-RADS classification on the oncological outcomes of SR vs. PA as single HCC first-line treatment. Methods: We retrospectively and blindly classified treatment-naïve single HCC that underwent SR or PA between 2010 and 2016 according to Li-RADS protocol. Overall survival (OS), recurrence free survival (RFS) and local recurrence after SR and PA were compared for each Li-RADS subclass before and after propensity-score matching (PS-M). Results: Considering the general population, SR showed better 5-year OS (68.3% vs. 52.2%; p = 0.049) and RFS (42.5% vs. 29.8%; p = 0.002), with lower incidence of local recurrence (8.2% vs. 44.4%; p < 0.001), despite a significantly higher frequency of clinically-relevant complications (12.8% vs. 1.9%; p = 0.002) and a higher Comprehensive Complication Index (12.1 vs. 2.2; p < 0.001). Focusing on different Li-RADS subclasses, we highlighted better 5-year OS (67.1% vs. 46.2%; p = 0.035), RFS (45.0% vs. 27.0% RFS; p < 0.001) and lower incidence of local recurrence (9.7% vs. 48.6%; p < 0.001) after SR for Li-RADS-5 HCCs, while these outcomes did not differ for Li-RADS-3/4 subclasses; such results were confirmed after PS-M. Conclusions: Our analysis suggests a potential prognostic role of Li-RADS classification, supporting SR over PA especially for Li-RADS-5 single HCC. Full article

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2020

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14 pages, 1915 KiB

Open AccessArticle

Real Life Prospective Evaluation of New Drug-Eluting Platform for Chemoembolization of Patients with Hepatocellular Carcinoma: PARIS Registry

by Thierry de Baere, Boris Guiu, Maxime Ronot, Patrick Chevallier, Géraldine Sergent, Illario Tancredi, Lambros Tselikas, Marco Dioguardi Burgio, Lucas Raynaud, Frederic Deschamps and Gontran Verset

Cancers 2020, 12(11), 3405; https://doi.org/10.3390/cancers12113405 - 17 Nov 2020

Cited by 12 | Viewed by 3309

Abstract

Background and aim: Transarterial chemoembolization with drug-eluting microspheres (DEM-TACE) is recommended for patients with BCLC stage B hepatocellular carcinoma (HCC) and stage 0-A unsuitable for curative treatments. We assessed efficacy and safety along with hepatobiliary toxicities (HBT) of DEM-TACE using a novel microsphere, [...] Read more.

Background and aim: Transarterial chemoembolization with drug-eluting microspheres (DEM-TACE) is recommended for patients with BCLC stage B hepatocellular carcinoma (HCC) and stage 0-A unsuitable for curative treatments. We assessed efficacy and safety along with hepatobiliary toxicities (HBT) of DEM-TACE using a novel microsphere, LifePearl^TM, loaded with anthracyclines. Materials and methods: 97 patients diagnosed with HCC were prospectively enrolled and treated using LifePearl^TM loaded with doxorubicin (77%) or idarubicin (23%). Safety and tolerability were assessed using CTCAE, HBT by CT/MRI scans, and tumor response by applying modified Response Evaluation Criteria in Solid Tumors (mRECIST). Follow-up was after 2 years. Results: Adverse events (AE) were reported in 73.2% of patients, majority being Grade 1–2. Grade ≥ 3 AE reported in 13.4% of patients were mainly related to postembolization syndrome. HBT were observed after 15.5% (29/187) of the DEM-TACEs. Objective response and disease control rates were 81% and 99%, respectively, as the best responses. Survival rates at one and two years were 81% and 66%, respectively, while the median overall survival (OS) was not reached. Median progression free survival was 13.7 months (95% CI: 11.3; 15.6) and median time to TACE untreatable progression was 16.7 months (95% CI: 12.7; not estimable (n.e.)). Conclusions: DEM-TACE using LifePearl^TM provides a high tumor response rate in HCC patients. HBT rates within or below previously reported results for cTACE and DEM-TACE indicate a good safety profile for LifePearl^TM. The trial was registered in National Library of Medicine (ID: NCT03053596). Full article

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15 pages, 1784 KiB

Open AccessReview

A Perspective on Cell Therapy and Cancer Vaccine in Biliary Tract Cancers (BTCs)

by Shuting Han, Suat Ying Lee, Who-Whong Wang, Yu Bin Tan, Rachel Hui Zhen Sim, Rachael Cheong, Cherlyn Tan, Richard Hopkins, John Connolly, Wai Ho Shuen and Han Chong Toh

Cancers 2020, 12(11), 3404; https://doi.org/10.3390/cancers12113404 - 17 Nov 2020

Cited by 20 | Viewed by 3362

Abstract

Biliary tract cancer (BTC) is a rare, but aggressive, disease that comprises of gallbladder carcinoma, intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma, with heterogeneous molecular profiles. Advanced disease has limited therapeutic options beyond first-line platinum-based chemotherapy. Immunotherapy has emerged as a viable option for many [...] Read more.

Biliary tract cancer (BTC) is a rare, but aggressive, disease that comprises of gallbladder carcinoma, intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma, with heterogeneous molecular profiles. Advanced disease has limited therapeutic options beyond first-line platinum-based chemotherapy. Immunotherapy has emerged as a viable option for many cancers with a similar unmet need. Therefore, we reviewed current understanding of the tumor immune microenvironment and recent advances in cellular immunotherapy and therapeutic cancer vaccines against BTC. We illustrated the efficacy of dendritic cell vaccination in one patient with advanced, chemorefractory, melanoma-associated antigen (MAGE)-positive gallbladder carcinoma, who was given multiple injections of an allogenic MAGE antigen-positive melanoma cell lysate (MCL)-based autologous dendritic cell vaccine combined with sequential anti-angiogenic therapy. This resulted in good radiological and tumor marker response and an overall survival of 3 years from diagnosis. We postulate the potential synergism of adding anti-angiogenic therapy, such as bevacizumab, to immunotherapy in BTC, as a rational scientific principle to positively modulate the tumor microenvironment to augment antitumor immunity. Full article

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