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Cancers
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Hepatobiliary Cancers
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Hepatobiliary Cancers

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 34557

Special Issue Editor

Prof. Dr. Arndt Vogel

E-Mail Website
Guest Editor
Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, 30625 Hannover, Germany
Interests: hepatobiliary cancer; colon cancer; targeted therapy; immunotherapy; precision medicine; translational medicine

Special Issue Information

Dear Colleagues,

The term “hepatobiliary cancers” encompasses both the primary malignant neoplasia of the liver (hepatocellular carcinoma and intrahepatic cholangiocarcinoma), as well as the cancers of the extrahepatic biliary system (distal cholangiocarcinoma and gall bladder cancer). Hepatobiliary cancers continue to constitute a major global healthcare problem, and their treatment requires interdisciplinary evaluation to develop individualized and tailored therapeutic concepts. The reasonable combination of appropriate surgical approaches, interventional/loco-regional strategies, and various lines of systemic therapies is required to achieve the best possible patient survival. In recent years, the approval of several tyrosine kinase inhibitors and antibodies such as ramucirumab have substantially changed the field of systemic therapy for patients with HCC, and the combination of bevacizumab and atezolizumab marks the transition from TKI monotherapy to immunotherapy-based combination therapies. So far, no genetic biomarkers to guide treatment decisions have been developed for HCC. In contrast, a thorough annotation of the genetic alterations of biliary tract cancers (BTCs) has been accomplished by several sequencing studies, and the results have laid the groundwork for the evaluation of novel, targeted therapeutic opportunities. Impressive results from pivotal phase II and III studies in pre-treated patients have confirmed that targeted therapies such as FGFR, BRAF, and IDH1 inhibitors are highly promising therapeutic options in genetically defined subgroups of BTC. Nevertheless, a better understanding of mechanisms that convey primary and secondary resistance will be crucial to improve up-front patient stratification, to prolong duration of response, and to implement reasonable co-treatment approaches.

This Special Issue aims to provide an overview of the most recent advances and future challenges for the diagnosis and treatment of hepatobiliary cancers. Manuscripts are welcome that report on original data or comprehensive literature reviews in the field focusing on local and systemic therapies, adjuvant therapies, targeted therapies, immunotherapies, and predictive and prognostic biomarkers, as well as molecular diagnostics including liquid biopsies.

Prof. Dr. Arndt Vogel
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • local, systemic, and adjuvant therapies
  • targeted therapies
  • immunotherapies
  • predictive/prognostic biomarkers
  • molecular diagnostics
  • liquid biopsies

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Published Papers (8 papers)

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Research

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13 pages, 270 KiB  
Article
Prognosis of Single Early-Stage Hepatocellular Carcinoma (HCC) with CEUS Inconclusive Imaging (LI-RADS LR-3 and LR-4) Is No Better than Typical HCC (LR-5)
by Eleonora Terzi, Alice Giamperoli, Massimo Iavarone, Simona Leoni, Ludovico De Bonis, Alessandro Granito, Antonella Forgione, Francesco Tovoli and Fabio Piscaglia
Cancers 2022, 14(2), 336; https://doi.org/10.3390/cancers14020336 - 11 Jan 2022
Cited by 11 | Viewed by 2110
Abstract
The American College of Radiology (ACR) released the Liver Imaging Report and Data System (LI-RADS) scheme, which categorizes hepatic nodules in risk classes from LR-1 to LR-5 (according to the degree of risk to be HCC) and LR-M (probable malignancy not specific for [...] Read more.
The American College of Radiology (ACR) released the Liver Imaging Report and Data System (LI-RADS) scheme, which categorizes hepatic nodules in risk classes from LR-1 to LR-5 (according to the degree of risk to be HCC) and LR-M (probable malignancy not specific for HCC). The aim of this study was to test whether HCC with different LR patterns on CEUS have different overall survival (OS) and recurrence-free survival (RFS). We retrospectively enrolled 167 patients with the first definitive diagnosis of single HCC (by using CT/MRI or histological techniques if CT/MRI were inconclusive) for whom CEUS examination was available. The median size of HCC lesions was 2.2 cm (range 1.0–7.2 cm). According to CEUS LI-RADS classification, 28 patients were in LR-3, 48 in LR-4, 83 in LR-5, and 8 in LR-M. Patient liver function and nodule characteristics were not statistically different between CEUS LI-RADS classes. Using univariate analysis, CEUS LI-RADS class was not found to be a predictor of survival (p = 0.347). In conclusion, HCC showing the CEUS LI-RADS classes LR-3 and LR-4 have no better clinical outcome than typical HCC. Such data support the EASL policy, aimed at conclusive diagnostic investigations of indeterminate nodules up to obtaining histological proof to avoid leaving aggressive HCC not timely treated. Full article
(This article belongs to the Special Issue Hepatobiliary Cancers)
15 pages, 2574 KiB  
Article
Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma
by Rebecca Marcus, Sammy Ferri-Borgogno, Abdel Hosein, Wai Chin Foo, Bidyut Ghosh, Jun Zhao, Kimal Rajapakshe, James Brugarolas, Anirban Maitra and Sonal Gupta
Cancers 2021, 13(22), 5709; https://doi.org/10.3390/cancers13225709 - 15 Nov 2021
Cited by 3 | Viewed by 3260
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a primary biliary malignancy that harbors a dismal prognosis. Oncogenic mutations of KRAS and loss-of-function mutations of BRCA1-associated protein 1 (BAP1) have been identified as recurrent somatic alterations in ICC. However, an autochthonous genetically engineered mouse model [...] Read more.
Intrahepatic cholangiocarcinoma (ICC) is a primary biliary malignancy that harbors a dismal prognosis. Oncogenic mutations of KRAS and loss-of-function mutations of BRCA1-associated protein 1 (BAP1) have been identified as recurrent somatic alterations in ICC. However, an autochthonous genetically engineered mouse model of ICC that genocopies the co-occurrence of these mutations has never been developed. By crossing Albumin-Cre mice bearing conditional alleles of mutant Kras and/or floxed Bap1, Cre-mediated recombination within the liver was induced. Mice with hepatic expression of mutant KrasG12D alone (KA), bi-allelic loss of hepatic Bap1 (BhomoA), and heterozygous loss of Bap1 in conjunction with mutant KrasG12D expression (BhetKA) developed primary hepatocellular carcinoma (HCC), but no discernible ICC. In contrast, mice with homozygous loss of Bap1 in conjunction with mutant KrasG12D expression (BhomoKA) developed discrete foci of HCC and ICC. Further, the median survival of BhomoKA mice was significantly shorter at 24 weeks when compared to the median survival of ≥40 weeks in BhetKA mice and approximately 50 weeks in BhomoA and KA mice (p < 0.001). Microarray analysis performed on liver tissue from KA and BhomoKA mice identified differentially expressed genes in the setting of BAP1 loss and suggests that deregulation of ferroptosis might be one mechanism by which loss of BAP1 cooperates with oncogenic Ras in hepato-biliary carcinogenesis. Our autochthonous model provides an in vivo platform to further study this lethal class of neoplasm. Full article
(This article belongs to the Special Issue Hepatobiliary Cancers)
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16 pages, 5114 KiB  
Article
CHPF Regulates the Aggressive Phenotypes of Hepatocellular Carcinoma Cells via the Modulation of the Decorin and TGF-β Pathways
by Chiung-Hui Liu, Bo-Rui Wu, Ying-Jui Ho, Yin-Hung Chu, Wei-Cheng Hsu, To-Jung Tseng, Ju-Pi Li and Wen-Chieh Liao
Cancers 2021, 13(6), 1261; https://doi.org/10.3390/cancers13061261 - 12 Mar 2021
Cited by 9 | Viewed by 3496
Abstract
Aberrant composition of glycans in the tumor microenvironment (TME) and abnormal expression of extracellular matrix proteins are hallmarks of hepatocellular carcinoma (HCC); however, the mechanisms responsible for establishing the TME remain unclear. We demonstrate that the chondroitin polymerizing factor (CHPF), an enzyme that [...] Read more.
Aberrant composition of glycans in the tumor microenvironment (TME) and abnormal expression of extracellular matrix proteins are hallmarks of hepatocellular carcinoma (HCC); however, the mechanisms responsible for establishing the TME remain unclear. We demonstrate that the chondroitin polymerizing factor (CHPF), an enzyme that mediates the elongation of chondroitin sulfate (CS), is a critical elicitor of the malignant characteristics of HCC as it modifies the potent tumor suppressor, decorin (DCN). CHPF expression is frequently downregulated in HCC tumors, which is associated with the poor overall survival of HCC patients. We observed that restoring CHPF expression suppressed HCC cell growth, migration, and invasion in vitro and in vivo. Mechanistic investigations revealed that TGF-β signaling is associated with CHPF-induced phenotype changes. We found that DCN, as a TGF-β regulator, is modified by CHPF, and that it affects the distribution of DCN on the surface of HCC cells. Importantly, our results confirm that CHPF and DCN expression levels are positively correlated in primary HCC tissues. Taken together, our results suggest that CHPF dysregulation contributes to the malignancy of HCC cells, and our study provides novel insights into the significance of CS, which affects DCN expression in the TME. Full article
(This article belongs to the Special Issue Hepatobiliary Cancers)
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12 pages, 1589 KiB  
Article
Namodenoson in Advanced Hepatocellular Carcinoma and Child–Pugh B Cirrhosis: Randomized Placebo-Controlled Clinical Trial
by Salomon M. Stemmer, Nebojsa S. Manojlovic, Mihai Vasile Marinca, Petar Petrov, Nelly Cherciu, Doina Ganea, Tudor Eliade Ciuleanu, Ioana Adriana Pusca, Muhammad Shaalan Beg, William T. Purcell, Adina-Emilia Croitoru, Rumyana Nedyalkova Ilieva, Sladjana Natošević, Amedeia Lavinir Nita, Dimitar Nikolaev Kalev, Zivit Harpaz, Motti Farbstein, Michael H. Silverman, David Bristol, Inbal Itzhak and Pnina Fishmanadd Show full author list remove Hide full author list
Cancers 2021, 13(2), 187; https://doi.org/10.3390/cancers13020187 - 7 Jan 2021
Cited by 32 | Viewed by 4516
Abstract
Namodenoson, an A3 adenosine-receptor agonist, showed promising results in advanced hepatocellular carcinoma (HCC) and moderate hepatic dysfunction (Child–Pugh B; CPB) in a phase I/II clinical study. This phase II study investigated namodenoson as second-line therapy in such patients. Patients were randomized 2:1 to [...] Read more.
Namodenoson, an A3 adenosine-receptor agonist, showed promising results in advanced hepatocellular carcinoma (HCC) and moderate hepatic dysfunction (Child–Pugh B; CPB) in a phase I/II clinical study. This phase II study investigated namodenoson as second-line therapy in such patients. Patients were randomized 2:1 to twice a day (BID) namodenoson (25 mg; n = 50) or placebo (n = 28). The primary endpoint (overall survival [OS]) was not met. Median OS was 4.1/4.3 months for namodenoson/placebo (hazard ratio [HR], 0.82; 95% confidence interval [CI] 0.49–1.38; p = 0.46). Pre-planned subgroup analysis of CPB7 patients (34 namodenoson-treated, 22 placebo-treated) showed a nonsignificant improvement in OS/progression-free survival (PFS). OS: 6.9 versus 4.3 months; HR, 0.81; 95% CI: 0.45–1.43, p = 0.46. PFS: 3.5 versus 1.9 months; HR, 0.89; 95% CI: 0.51–1.55, p = 0.67 (log-rank test). The difference in 12-month OS was significant (44% versus 18%, p = 0.028). Response rates were determined in patients for whom ≥ 1 assessment post-baseline was available (34 namodenoson-treated, 21 placebo-treated). Partial response was achieved by 3/34 (8.8%) and 0/21 (0%) patients, respectively. Namodenoson was well-tolerated, with a safety profile comparable to that of the placebo group. No treatment-related deaths were reported; no patients withdrew due to toxicity. In conclusion, namodenoson demonstrated a favorable safety profile and a preliminary efficacy signal in HCC CPB. Full article
(This article belongs to the Special Issue Hepatobiliary Cancers)
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16 pages, 2306 KiB  
Article
Serum Myostatin Predicts the Risk of Hepatocellular Carcinoma in Patients with Alcoholic Cirrhosis: A Multicenter Study
by Ji Hyun Kim, Seong Hee Kang, Minjong Lee, Gi Soo Youn, Tae Suk Kim, Baek Gyu Jun, Moon Young Kim, Young Don Kim, Gab Jin Cheon, Dong Joon Kim, Soon Koo Baik, Dae Hee Choi and Ki Tae Suk
Cancers 2020, 12(11), 3347; https://doi.org/10.3390/cancers12113347 - 12 Nov 2020
Cited by 11 | Viewed by 2115
Abstract
Background and Aim: Previous studies reported that serum myostatin is associated with sarcopenia. We aimed to elucidate the association between serum myostatin levels and hepatocellular carcinoma (HCC) development in patients with alcoholic liver cirrhosis (ALC). Methods: This retrospective, multicenter study assessed 1077 Asian [...] Read more.
Background and Aim: Previous studies reported that serum myostatin is associated with sarcopenia. We aimed to elucidate the association between serum myostatin levels and hepatocellular carcinoma (HCC) development in patients with alcoholic liver cirrhosis (ALC). Methods: This retrospective, multicenter study assessed 1077 Asian ALC patients enrolled from 2007 to 2017. The primary endpoint was the development of HCC within 5 years. Cox proportional hazards model analyses were used to assess the association of serum myostatin levels and HCC development. The time-dependent areas under the receiver operating characteristic curve (AUROC) of serum myostatin for 5-year HCC development were calculated. Serum myostatin levels were measured using an enzyme-linked immunosorbent assay with samples collected on the index date. Results: During a median follow-up of 2.5 years, 5-year cumulative HCC incidence rates were 6.7% in the total population. The median level of serum myostatin was 3.3 ng/mL (interquartile, 2.1–5.2 ng/mL). The AUROC of serum myostatin for 5-year HCC development was 0.78 (95% confidence interval [CI], 0.76–0.81). In Cox proportional hazards model analyses, age, gender, platelet counts, and serum myostatin levels were independent risk factors for HCC development (adjusted hazard ratios [HRs] of age, male gender, platelet counts, and serum myostatin: 1.03, 2.79, 0.996, 1.18, respectively; all p < 0.05). Patients with high myostatin levels had a significantly higher risk of 5-year HCC development than those with low myostatin levels (HR 7.53, p < 0.001). Conclusion: Higher serum myostatin levels were significantly associated with a higher risk of developing HCC in ALC patients, which could identify high-risk patients who need stringent surveillance. Full article
(This article belongs to the Special Issue Hepatobiliary Cancers)
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Review

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20 pages, 1086 KiB  
Review
Tertiary Prevention of HCC in Chronic Hepatitis B or C Infected Patients
by Wei Teng, Yen-Chun Liu, Wen-Juei Jeng and Chien-Wei Su
Cancers 2021, 13(7), 1729; https://doi.org/10.3390/cancers13071729 - 6 Apr 2021
Cited by 15 | Viewed by 6432
Abstract
Hepatocellular carcinoma (HCC) ranks as a leading cause of common cancer and cancer-related death. The major etiology of HCC is due to chronic hepatitis virus including HBV and HCV infections. Scheduled HCC surveillance in high risk populations improves the early detection rate and [...] Read more.
Hepatocellular carcinoma (HCC) ranks as a leading cause of common cancer and cancer-related death. The major etiology of HCC is due to chronic hepatitis virus including HBV and HCV infections. Scheduled HCC surveillance in high risk populations improves the early detection rate and the feasibility of curative treatment. However, high HCC recurrence rate still accounts for the poor prognosis of HCC patients. In this article, we critically review the pathogenesis of viral hepatitis-related hepatocellular carcinoma and the evidence of tertiary prevention efficacy by current available antiviral treatment, and discuss the knowledge gap in viral hepatitis-related HCC tertiary prevention. Full article
(This article belongs to the Special Issue Hepatobiliary Cancers)
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11 pages, 249 KiB  
Review
The New Immuno-Oncology-Based Therapies and Their Perspectives in Hepatocellular Carcinoma
by Philippe Merle
Cancers 2021, 13(2), 238; https://doi.org/10.3390/cancers13020238 - 11 Jan 2021
Cited by 14 | Viewed by 3647
Abstract
Hepatocellular carcinoma is a poor prognosis tumor. Systemic therapies are frequently used due to frequent recurrences after surgical or radiologic treatments. Anti-angiogenic tyrosine kinase inhibitors have shown efficacy in monotherapy, but with very low rates of long survival and exceptional recovery. Immuno-oncology based [...] Read more.
Hepatocellular carcinoma is a poor prognosis tumor. Systemic therapies are frequently used due to frequent recurrences after surgical or radiologic treatments. Anti-angiogenic tyrosine kinase inhibitors have shown efficacy in monotherapy, but with very low rates of long survival and exceptional recovery. Immuno-oncology based on immune checkpoint inhibitors has revolutionized the systemic therapies since showing long survival rates without any tumor progression or recurrence for some patients in partial or complete response, and possibly for some patients in stable disease. However, the rate of responders under immuno-oncology monotherapy is too low to increase significantly the median overall survival of the treated patients. The immuno-oncology-based combinations with different types of immune checkpoint inhibitors (PD-1/PD-L1 and CTLA-4 inhibitors such as nivolumab, pembrolizumab, atezolizumab, durvalumab, ipilimumab, tremelimumab), or the association of immune checkpoint inhibitors plus anti-angiogenic agents (bevacizumab, lenvatinib, cabozantinib), have led to a breakthrough in the treatment of hepatocellular carcinoma. Indeed, the first phase-3 trial, combining atezolizumab with bevacizumab, has dramatically changed the outcome of patients. Data from several other types of combinations assessed in phase-3 trials are pending, and if positive, will drastically arm the physicians to efficiently treat the patients, and disrupt the current algorithm of hepatocellular carcinoma treatment. Full article
(This article belongs to the Special Issue Hepatobiliary Cancers)
21 pages, 18050 KiB  
Review
Pathophysiology and Imaging Findings of Bile Duct Necrosis: A Rare but Serious Complication of Transarterial Therapy for Liver Tumors
by Satoshi Kobayashi, Kazuto Kozaka, Toshifumi Gabata, Osamu Matsui, Wataru Koda, Miho Okuda, Kenichiro Okumura, Takumi Sugiura and Takahiro Ogi
Cancers 2020, 12(9), 2596; https://doi.org/10.3390/cancers12092596 - 11 Sep 2020
Cited by 10 | Viewed by 7782
Abstract
Bile duct necrosis (BDN) with biloma formation is a type of ischemic bile duct injury that is one of the serious complications associated with transarterial therapies, such as transcatheter chemoembolization therapy (TACE), and radioembolization for hepatocellular carcinoma (HCC) and hepatic arterial infusion chemotherapy [...] Read more.
Bile duct necrosis (BDN) with biloma formation is a type of ischemic bile duct injury that is one of the serious complications associated with transarterial therapies, such as transcatheter chemoembolization therapy (TACE), and radioembolization for hepatocellular carcinoma (HCC) and hepatic arterial infusion chemotherapy (HAIC) for metastatic liver cancer from colorectal carcinoma. In terms of the occurrence of BDN and subsequent biloma formation, ischemic injury to the peribiliary vascular plexus (PBP), the supporting vessel of bile duct epithelium, is thought to be intimately associated. In this paper, we first describe the anatomy, blood supply, and function of the intrahepatic bile duct, and then illustrate the pathophysiology of BDN, and finally present the imaging findings of BDN. Under the process of BDN formation, ischemia of the PBP induces the disruption of the bile duct epithelial protection mechanism that causes coagulation and fibrinoid necrosis of the surrounding tissue by the detergent action of exuded bile acids, and eventually a biloma forms. Once BDN occurs, persistent tissue damage to the surrounding bile duct is induced by imbibed bile acids, and portal vein thrombosis may also be observed. On pre-contrast and contrast-enhanced computed tomography (CT), BDN shows similar findings to intrahepatic bile duct dilatation, and, therefore, it is sometimes misdiagnosed. Differentiation of imaging findings on CT and ultrasound (US)/magnetic resonance (MR) imaging/MR cholangiopancreatography (MRCP) is important for correct diagnosis of BDN. Full article
(This article belongs to the Special Issue Hepatobiliary Cancers)
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