Research

17 pages, 2011 KiB

Open AccessArticle

Ring Finger Protein 125 Is an Anti-Proliferative Tumor Suppressor in Hepatocellular Carcinoma

by Takahiro Kodama, Michiko Kodama, Nancy A. Jenkins, Neal G. Copeland, Huanhuan Joyce Chen and Zhubo Wei

Cancers 2022, 14(11), 2589; https://doi.org/10.3390/cancers14112589 - 24 May 2022

Cited by 5 | Viewed by 1971

Abstract

Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide and the only cancer with an increasing incidence in the United States. Recent advances in sequencing technology have enabled detailed profiling of liver cancer genomes and revealed extensive inter- and intra-tumor heterogeneity, making [...] Read more.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide and the only cancer with an increasing incidence in the United States. Recent advances in sequencing technology have enabled detailed profiling of liver cancer genomes and revealed extensive inter- and intra-tumor heterogeneity, making it difficult to identify driver genes for HCC. To identify HCC driver genes, we performed transposon mutagenesis screens in a mouse HBV model of HCC and discovered many candidate cancer genes (SB/HBV-CCGs). Here, we show that one of these genes, RNF125 is a potent anti-proliferative tumor suppressor gene in HCC. RNF125 is one of nine CCGs whose expression was >3-fold downregulated in human HCC. Depletion of RNF125 in immortalized mouse liver cells led to tumor formation in transplanted mice and accelerated growth of human liver cancer cell lines, while its overexpression inhibited their growth, demonstrating the tumor-suppressive function of RNF125 in mouse and human liver. Whole-transcriptome analysis revealed that RNF125 transcriptionally suppresses multiple genes involved in cell proliferation and/or liver regeneration, including Egfr, Met, and Il6r. Blocking Egfr or Met pathway expression inhibited the increased cell proliferation observed in RNF125 knockdown cells. In HCC patients, low expression levels of RNF125 were correlated with poor prognosis demonstrating an important role for RNF125 in HCC. Collectively, our results identify RNF125 as a novel anti-proliferative tumor suppressor in HCC. Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

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12 pages, 1623 KiB

Open AccessEditor’s ChoiceArticle

Interleukin-6 Is a Circulating Prognostic Biomarker for Hepatocellular Carcinoma Patients Treated with Combined Immunotherapy

by Yuta Myojin, Takahiro Kodama, Ryotaro Sakamori, Kazuki Maesaka, Takayuki Matsumae, Yoshiyuki Sawai, Yasuharu Imai, Kazuyoshi Ohkawa, Masanori Miyazaki, Satoshi Tanaka, Eiji Mita, Seiichi Tawara, Takayuki Yakushijin, Yasutoshi Nozaki, Hideki Hagiwara, Yuki Tahata, Ryoko Yamada, Hayato Hikita, Tomohide Tatsumi and Tetsuo Takehara

Cancers 2022, 14(4), 883; https://doi.org/10.3390/cancers14040883 - 10 Feb 2022

Cited by 35 | Viewed by 3363

Abstract

Atezolizumab/bevacizumab (Atezo/Bev) combination therapy has become a front-line therapy for advanced hepatocellular carcinoma (HCC), but approximately 20% of patients are nonresponders. We investigated circulating biomarkers to predict therapeutic outcomes. We performed simultaneous measurement of 34 proteins using a multiplex bead-based immunoassay in baseline [...] Read more.

Atezolizumab/bevacizumab (Atezo/Bev) combination therapy has become a front-line therapy for advanced hepatocellular carcinoma (HCC), but approximately 20% of patients are nonresponders. We investigated circulating biomarkers to predict therapeutic outcomes. We performed simultaneous measurement of 34 proteins using a multiplex bead-based immunoassay in baseline plasma from 34 patients who underwent Atezo/Bev therapy as first- or second-line treatment. Logistic regression analysis showed that plasma IL-6 and interferon alpha (IFNα) levels were significant predictors of non-responders (odds ratio of 13.33 and FDR p = 0.021 for IL-6 and IFNα). The progression-free survival (PFS) and overall survival (OS) of patients with high IL-6 levels were significantly shorter than those of patients with low IL-6 levels. Next, we measured baseline plasma IL-6 levels in 64 HCC patients who underwent Atezo/Bev therapy by ELISA. The IL-6-high group showed higher female ratio, AST levels, tumor markers, Child–Pugh score, and vascular invasion ratio. The PFS and OS of the IL-6-high group were significantly shorter than those of the IL-6-low group. Multivariate Cox proportional hazards analysis showed that IL-6 level and age were independent risk factors for disease progression (hazard ratio of 2.785 and p = 0.015 for IL-6, and hazard ratio 0.306 and p = 0.03 for age). In conclusion, circulating IL-6 levels are a novel prognostic biomarker for advanced HCC patients who undergo combined immunotherapy. Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

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12 pages, 1174 KiB

Open AccessFeature PaperArticle

Validation of IL-7R as an Immunological Biomarker for Human Pancreatic Ductal Adenocarcinoma

by Sung-Ill Jang, Jae-Hee Cho, So-Young Kim, In-Young Hong, Joon-Seong Park, Hye-Sun Lee, Goeun Park, Jong-Kyoung Kim, Hyung-Keun Lee and Dong-Ki Lee

Cancers 2022, 14(3), 853; https://doi.org/10.3390/cancers14030853 - 08 Feb 2022

Cited by 3 | Viewed by 2267

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer for which no early diagnostic method is available. The immune surveillance hypothesis suggests that the immune system plays crucial roles in tumor development and progression. We validated a PDAC-specific biomarker derived from peripheral blood mononuclear [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer for which no early diagnostic method is available. The immune surveillance hypothesis suggests that the immune system plays crucial roles in tumor development and progression. We validated a PDAC-specific biomarker derived from peripheral blood mononuclear cells (PBMCs) to facilitate early PDAC diagnosis. mRNA levels of interleukin-7R (IL-7R), reportedly a potential immunological marker for PDAC, were measured in PBMCs isolated prospectively from healthy controls (n = 100) and patients with PDAC (n = 135), pancreatic cysts (n = 82), chronic pancreatitis (n = 42), acute pancreatitis (n = 47), and other malignancies (n = 116). The IL-7R level was significantly higher in patients with PDAC than in healthy controls, patients with benign pancreatic disease, and patients with other malignancies. As diagnostic parameters, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for IL-7R were 58.5%, 92%, 90.8%, 62.2%, and 72.8%, respectively. The area under the receiver operating characteristic curve (AUROC) was 0.766. IL-7R levels did not differ between resectable and unresectable PDAC cases. The combined measurement of IL-7R and carbohydrate antigen 19-9 (CA19-9) significantly improved the diagnostic parameters and AUROC compared with the use of IL-7R or CA19-9 alone. IL-7R is significantly upregulated in PBMCs in patients with PDAC, and it may be a novel diagnostic marker for PDAC. The combined use of IL-7R and CA19-9 enhanced the diagnostic performance. Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

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21 pages, 5540 KiB

Open AccessArticle

Molecular Pathogenesis and Regulation of the miR-29-3p-Family: Involvement of ITGA6 and ITGB1 in Intra-Hepatic Cholangiocarcinoma

by Yuto Hozaka, Naohiko Seki, Takako Tanaka, Shunichi Asai, Shogo Moriya, Tetsuya Idichi, Masumi Wada, Kiyonori Tanoue, Yota Kawasaki, Yuko Mataki, Hiroshi Kurahara and Takao Ohtsuka

Cancers 2021, 13(11), 2804; https://doi.org/10.3390/cancers13112804 - 04 Jun 2021

Cited by 21 | Viewed by 2695

Abstract

The aggressive nature of intrahepatic cholangiocarcinoma (ICC) renders it a particularly lethal solid tumor. Searching for therapeutic targets for ICC is an essential challenge in the development of an effective treatment strategy. Our previous studies showed that the miR-29-3p-family members (miR-29a-3p [...] Read more.

The aggressive nature of intrahepatic cholangiocarcinoma (ICC) renders it a particularly lethal solid tumor. Searching for therapeutic targets for ICC is an essential challenge in the development of an effective treatment strategy. Our previous studies showed that the miR-29-3p-family members (miR-29a-3p, miR-29b-3p and miR-29c-3p) are key tumor-suppressive microRNAs that control many oncogenic genes/pathways in several cancers. In this study, we searched for therapeutic targets for ICC using the miR-29-3p-family as a starting point. Our functional studies of cell proliferation, migration and invasion confirmed that the miR-29-3p-family act as tumor-suppressors in ICC cells. Moreover, in silico analysis revealed that “focal adhesion”, “ECM-receptor”, “endocytosis”, “PI3K-Akt signaling” and “Hippo signaling” were involved in oncogenic pathways in ICC cells. Our analysis focused on the genes for integrin-α6 (ITGA6) and integrin-β1 (ITGB1), which are involved in multiple pathways. Overexpression of ITGA6 and ITGB1 enhanced malignant transformation of ICC cells. Both ITGA6 and ITGB1 were directly regulated by the miR-29-3p-family in ICC cells. Interestingly, expression of ITGA6/ITGB1 was positively controlled by the transcription factor SP1, and SP1 was negatively controlled by the miR-29-3p-family. Downregulation of the miR-29-3p-family enhanced SP1-mediated ITGA6/ITGB1 expression in ICC cells. MicroRNA-based exploration is an attractive strategy for identifying therapeutic targets for ICC. Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

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19 pages, 3248 KiB

Open AccessArticle

Histone Methyltransferase G9a-Promoted Progression of Hepatocellular Carcinoma Is Targeted by Liver-Specific Hsa-miR-122

by Lan-Ting Yuan, Wei-Jiunn Lee, Yi-Chieh Yang, Bo-Rong Chen, Ching-Yao Yang, Min-Wei Chen, Ji-Qing Chen, Michael Hsiao, Ming-Hsien Chien and Kuo-Tai Hua

Cancers 2021, 13(10), 2376; https://doi.org/10.3390/cancers13102376 - 14 May 2021

Cited by 12 | Viewed by 2423

Abstract

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers, which is the second most lethal tumor worldwide. Epigenetic deregulation is a common trait observed in HCC. Recently, increasing evidence suggested that the G9a histone methyltransferase might be a novel regulator of [...] Read more.

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers, which is the second most lethal tumor worldwide. Epigenetic deregulation is a common trait observed in HCC. Recently, increasing evidence suggested that the G9a histone methyltransferase might be a novel regulator of HCC development. However, several HCC cell lines were recently noted to have HeLa cell contamination or to have been derived from non-hepatocellular origin, suggesting that functional validation of G9a in proper HCC models is still required. Herein, we first confirmed that higher G9a messenger RNA and protein expression levels were correlated with poor overall survival (OS) and disease-free survival (DFS) rates of HCC patients from The Cancer Genome Atlas (TCGA) dataset and our recruited HCC cohort. In an in vitro functional evaluation of HCC cells, HCC36 (hepatitis B virus-positive (HBV+) and Mahlavu (HBV−)) cells showed that G9a participated in promoting cell proliferation, colony formation, and migration/invasion abilities. Moreover, orthotopic inoculation of G9a-depleted Mahlavu cells in NOD-SCID mice also resulted in a significantly decreased tumor burden compared to the control group. Furthermore, after surveying microRNA (miRNA; miR) prediction databases, we identified the liver-specific miR-122 as a G9a-targeting miRNA. In various HCC cell lines, we observed that miR-122 expression levels tended to be inversely correlated to G9a expression levels. In clinical HCC specimens, a significant inverse correlation of miR-122 and G9a mRNA expression levels was also observed. Functionally, the colony formation and invasive ability were attenuated in miR-122-overexpressing HCC cells. HCC patients with low miR-122 and high G9a expression levels had the worst OS and DFS rates compared to others. Together, our results confirmed the importance of altered G9a expression during HCC progression and discovered that a novel liver-specific miR-122-G9a regulatory axis exists. Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

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9 pages, 731 KiB

Open AccessArticle

Circulating Cell-Free DNA as a Prognostic Biomarker in Resectable Ampullary Cancer

by Bor-Uei Shyr, Bor-Shiuan Shyr, Shih-Chin Chen, Shih-Ching Chang, Yi-Ming Shyr and Shin-E Wang

Cancers 2021, 13(10), 2313; https://doi.org/10.3390/cancers13102313 - 12 May 2021

Cited by 2 | Viewed by 1304

Abstract

Circulating cell-free DNA (cfDNA) in ampullary cancer patients was measured to clarify the correlation between cfDNA and clinicopathological factors and the impact of cfDNA on survival outcomes. Patients with ampullary cancer undergoing pancreaticoduodenectomy were included. Correlations between cfDNA and clinicopathological and prognostic factors [...] Read more.

Circulating cell-free DNA (cfDNA) in ampullary cancer patients was measured to clarify the correlation between cfDNA and clinicopathological factors and the impact of cfDNA on survival outcomes. Patients with ampullary cancer undergoing pancreaticoduodenectomy were included. Correlations between cfDNA and clinicopathological and prognostic factors were determined. The cfDNA levels in patients ranged from 1282 to 21,674 copies/mL, with a median of 6687 copies/mL. The cfDNA level was significantly higher in patients with lymph node involvement, lymphovascular invasion, abnormal serum carcinoembryonic antigen (CEA) level, and stage II and III cancer. Poor prognostic factors for ampullary cancer included high cfDNA > 6687 copies/mL, lymph node involvement, abnormal serum CEA > 5 ng/mL, and advanced stage II and III cancer. The 1- and 5-year survival rates were 92.0% and 66.5%, respectively, for patients with low cfDNA < 6687 copies/mL and 84.0% and 49.9%, respectively, for patients with high cfDNA > 6687 copies/mL (p < 0.001). After multivariate analysis, only the cfDNA level and stage were independent prognostic factors of ampullary cancer. Thus, the cfDNA level could act as a surrogate marker of both disease extent and biological aggressiveness of ampullary cancer. Moreover, cfDNA plays a significant role in the prognosis of resectable ampullary cancer. Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

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18 pages, 6700 KiB

Open AccessArticle

Programmed Death Ligand-1 (PD-L1) Is an Independent Negative Prognosticator in Western-World Gallbladder Cancer

by Thomas Albrecht, Fritz Brinkmann, Michael Albrecht, Anke S. Lonsdorf, Arianeb Mehrabi, Katrin Hoffmann, Yakup Kulu, Alphonse Charbel, Monika N. Vogel, Christian Rupp, Bruno Köhler, Christoph Springfeld, Peter Schirmacher, Stephanie Roessler and Benjamin Goeppert

Cancers 2021, 13(7), 1682; https://doi.org/10.3390/cancers13071682 - 02 Apr 2021

Cited by 16 | Viewed by 2659

Abstract

Inhibition of the programmed cell death protein-1/ligand-1 (PD-1/PD-L1) axis has opened a new era in the treatment of solid cancers. However, there is no data on the expression and relevance of PD-L1 in Western gallbladder cancer (GBC). We assessed PD-L1 immunohistochemically in 131 [...] Read more.

Inhibition of the programmed cell death protein-1/ligand-1 (PD-1/PD-L1) axis has opened a new era in the treatment of solid cancers. However, there is no data on the expression and relevance of PD-L1 in Western gallbladder cancer (GBC). We assessed PD-L1 immunohistochemically in 131 GBC patients as Tumor Proportion Score (TPS), Immune Cell Score (IC) and Combined Positivity Score (CPS). Tumor cells expressed PD-L1 in a subset of 14.7% GBC patients at a TPS cut-off of 1%. Higher PD-L1 levels above 10% and 25% TPS were reached in 4.7% and 3.1% of GBC cases, respectively. At a 10% cut-off, TPS was associated with distinct histomorphological subtypes and correlated with poor tumor differentiation. Survival analysis revealed a TPS above 10% to be a highly significant and independent negative prognosticator in GBC. PD-L1 expression was associated with increased CD4⁺, CD8⁺ and PD-1⁺ immune cell densities. In 14.8% of the cases, scattered immune cells expressed T-cell immunoreceptor with Ig and ITIM domains (TIGIT), which was correlated to tumoral expression of its ligand CD155. We here show that a high PD-L1 expression confers a negative prognostic value in Western-world GBC and highlight the TIGIT/CD155 immune checkpoint as a potential new target for GBC immunotherapy. Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

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9 pages, 897 KiB

Open AccessArticle

Prognostic Value of Carcinoembryonic Antigen (CEA) and Carbohydrate Antigen 19-9 (CA 19-9) in Gallbladder Cancer; 65 IU/mL of CA 19-9 Is the New Cut-Off Value for Prognosis

by Myongjin Kim, Hongbeom Kim, Youngmin Han, Heeju Sohn, Jae Seung Kang, Wooil Kwon and Jin-Young Jang

Cancers 2021, 13(5), 1089; https://doi.org/10.3390/cancers13051089 - 04 Mar 2021

Cited by 8 | Viewed by 2413

Abstract

Due to the lack of appropriate tumor markers with optimal cut-off values to predict the prognosis of gallbladder cancer (GBC), this study aimed to demonstrate the relationship between prognosis and the levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9), and [...] Read more.

Due to the lack of appropriate tumor markers with optimal cut-off values to predict the prognosis of gallbladder cancer (GBC), this study aimed to demonstrate the relationship between prognosis and the levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9), and to determine optimal thresholds. In total, 539 patients diagnosed with GBC were examined. The relationship between tumor marker levels and overall survival (OS) was analyzed. The C-tree method was used to suggest tumor marker thresholds, and multivariate analysis was conducted to identify prognostic factors for overall survival. The mean age of the patients was 65.3 years, and the 5-year overall survival rate in all patients was 68.9%. Following the C-tree method, the optimal cut-off value was set at 5 IU/mL for CEA and at 65 IU/mL for CA 19-9. Multivariate analysis revealed that age, CA 19-9 level, operative method, T stage, and N stage were significant prognostic factors for OS. Consequently, CA 19-9 had a stronger association with prognosis than CEA, and 65 IU/mL for CA 19-9 may be suggestive in evaluating the prognosis of GBC. Moreover, it could be an effective indicator for determining the surgical extent necessary and the need for adjuvant treatment. Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

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12 pages, 3452 KiB

Open AccessArticle

Stage-Specific Value of Carbohydrate Antigen 19-9 and Carcinoembryonic Antigen Serum Levels on Survival and Recurrence in Pancreatic Cancer: A Single Center Study and Meta-Analysis

by Labrinus van Manen, Jesse V. Groen, Hein Putter, Martin Pichler, Alexander L. Vahrmeijer, Bert A. Bonsing and J. Sven D. Mieog

Cancers 2020, 12(10), 2970; https://doi.org/10.3390/cancers12102970 - 14 Oct 2020

Cited by 14 | Viewed by 2442

Abstract

This study aimed to determine the stage-specific prognostic value of carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) serum levels at diagnosis on overall survival (OS) and time to local recurrence or distant metastases in patients with pancreatic ductal adenocarcinoma (PDAC). Consecutive PDAC [...] Read more.

This study aimed to determine the stage-specific prognostic value of carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) serum levels at diagnosis on overall survival (OS) and time to local recurrence or distant metastases in patients with pancreatic ductal adenocarcinoma (PDAC). Consecutive PDAC patients, discussed at multidisciplinary team meetings from 2013 through 2017, were reviewed. Prognostic factors were stage-specific (resection vs. advanced PDAC) evaluated in Cox proportional hazard models. Additionally, a systematic literature search and meta-analysis was performed, as current literature is lacking a complete overview of used cut-off values and the added value of CEA as prognostic marker. In the retrospective cohort, elevated CA19-9 (>305 kU/L) level was independently associated with poor OS (Hazard ratio (HR): 1.72(1.31–2.26)) and early recurrence (HR: 1.74(1.06–2.86)), whereas CEA was not significantly associated. The meta-analysis showed that both elevated CA19-9 and CEA serum levels were predictors for poor OS (pooled HR: 1.29(1.17–1.42) and HR: 1.51(1.33–1.73), respectively). In the resected cohort, elevated CA19-9 level was significantly associated with early recurrence (pooled HR: 2.41(1.77–3.29)), whereas CEA was not. Elevated CA19-9 serum level appear to be an independent prognostic factor for poor OS and early recurrence in PDAC patients, whereas the prognostic value of CEA is disputable. Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

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Review

Jump to: Research, Other

35 pages, 850 KiB

Open AccessReview

Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature

by Giovanni Vitale, Alessandro Mattiaccio, Amalia Conti, Laura Turco, Marco Seri, Fabio Piscaglia and Maria Cristina Morelli

Cancers 2022, 14(14), 3421; https://doi.org/10.3390/cancers14143421 - 14 Jul 2022

Cited by 9 | Viewed by 4283

Abstract

The family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport defects. Specific genetic pathways potentially cause many otherwise unexplained cholestasis or hepatobiliary tumours in a healthy liver. Lately, next-generation sequencing and [...] Read more.

The family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport defects. Specific genetic pathways potentially cause many otherwise unexplained cholestasis or hepatobiliary tumours in a healthy liver. Lately, next-generation sequencing and whole-exome sequencing have improved the diagnostic procedures of familial intrahepatic cholestasis (FIC), as well as the discovery of several genes responsible for FIC. Moreover, mutations in these genes, even in the heterozygous status, may be responsible for cryptogenic cholestasis in both young and adults. Mutations in FIC genes can influence serum and hepatic levels of bile acids. Experimental studies on the NR1H4 gene have shown that high bile acids concentrations cause excessive production of inflammatory cytokines, resistance to apoptosis, and increased cell regeneration, all risk conditions for developing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). NR1H4 gene encodes farnesoid X-activated receptor having a pivotal role in bile salts synthesis. Moreover, HCC and CCA can emerge in patients with several FIC genes such as ABCB11, ABCB4 and TJP2. Herein, we reviewed the available data on FIC-related hepatobiliary cancers, reporting on genetics to the pathophysiology, the risk factors and the clinical presentation. Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

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8 pages, 481 KiB

Open AccessReview

Risk of Hepatocellular Carcinoma in Patients with Porphyria: A Systematic Review

by Daryl Ramai, Smit S. Deliwala, Saurabh Chandan, Janice Lester, Jameel Singh, Jayanta Samanta, Sara di Nunzio, Fabio Perversi, Francesca Cappellini, Aashni Shah, Michele Ghidini, Rodolfo Sacco, Antonio Facciorusso and Luca Giacomelli

Cancers 2022, 14(12), 2947; https://doi.org/10.3390/cancers14122947 - 15 Jun 2022

Cited by 10 | Viewed by 2634

Abstract

Acute porphyrias are a group of metabolic disorders resulting in defective porphyrin synthesis and reduced heme production, which carries a risk of malignancy. Porphyrias are inborn defects in the heme biosynthesis pathway resulting in neurovisceral manifestations and cutaneous photosensitivity attacks with multi-systemic involvement. [...] Read more.

Acute porphyrias are a group of metabolic disorders resulting in defective porphyrin synthesis and reduced heme production, which carries a risk of malignancy. Porphyrias are inborn defects in the heme biosynthesis pathway resulting in neurovisceral manifestations and cutaneous photosensitivity attacks with multi-systemic involvement. Its estimated prevalence nears 5 per 100,000 patients worldwide. Subclinical liver disease is common, which can progress into transaminitis, fibrosis, cirrhosis, and malignancy. However, data on the incidence of primary liver cancer are lacking. We aim to determine the risk of hepatocellular carcinoma (HCC) in patients with porphyria. A systematic review and pooled analysis were conducted through 2021 on studies assessing blood tests, imaging, cancer development, liver transplant, surgical resection, and outcomes in porphyria. In total, 19 studies, which included 7381 patients with porphyria (3476 females), were considered for the final review. In eight studies, alpha-fetoprotein levels were elevated between 200 and 1000 IU/mL. Of the total cohort of patients with porphyria, primary liver cancer was diagnosed in 351 patients (4.8%), of whom 243 (3.3% of the total) were found to have HCC. A subset of patients was found to have cholangiocarcinoma (n = 18; 0.3% of the total). Interestingly, advanced liver disease or cirrhosis was not a prerequisite for the formation of HCC in a small group of patients. Of the total cohort, 30 patients underwent liver resection, 48 patients underwent liver transplantation, and 327 patients died. Patients with porphyria are at risk of developing primary liver malignancy. Further studies should aim to develop diagnostic and prognostic models aimed at the early detection of HCC in porphyria. Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

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18 pages, 645 KiB

Open AccessReview

Biomarkers for the Detection and Management of Hepatocellular Carcinoma in Patients Treated with Direct-Acting Antivirals

by Loraine Kay D. Cabral, Luca Grisetti, Muhammad Yogi Pratama, Claudio Tiribelli and Devis Pascut

Cancers 2022, 14(11), 2700; https://doi.org/10.3390/cancers14112700 - 30 May 2022

Cited by 3 | Viewed by 2320

Abstract

Hepatocellular carcinoma (HCC) is the sixth-most common type of cancer worldwide and chronic Hepatitis C virus (HCV) represents the main etiological factor in developed countries. HCV promotes hepatocarcinogenesis through persistent liver inflammation and dysregulation of cell signaling pathways. The introduction of direct-acting antivirals [...] Read more.

Hepatocellular carcinoma (HCC) is the sixth-most common type of cancer worldwide and chronic Hepatitis C virus (HCV) represents the main etiological factor in developed countries. HCV promotes hepatocarcinogenesis through persistent liver inflammation and dysregulation of cell signaling pathways. The introduction of direct-acting antivirals (DAAs) resulted in a significant improvement in the eradication of the virus, with an expected reduction of HCC incidence. However, the risk of HCC development can persist after DAA treatment. Recent studies have investigated the potential use of molecular biomarkers that predict HCC occurrence or recurrence helping the stratification of patients under surveillance. This review aimed to summarize all pre-clinical exploration of predictive biomarkers to identify DAA-treated patients at risk for HCC development. Dysregulated microRNAs, lncRNAs, histone modifications, cytokines, proteins, and sphingolipids represent various classes of HCC risk predictors identified in two different biological sources (tissue and serum). The non-invasive serum markers can provide a more accessible means to perform clinical monitoring and predict the risk of HCC. In addition, conditions like cirrhosis, predisposing to HCC, strongly correlate with most of the molecular predictors identified, supporting the value of these molecules as possible biomarkers of HCC in DAA-treated patients. Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

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16 pages, 524 KiB

Open AccessEditor’s ChoiceReview

The Impact of Biomarkers in Pancreatic Ductal Adenocarcinoma on Diagnosis, Surveillance and Therapy

by Niklas Sturm, Thomas J. Ettrich and Lukas Perkhofer

Cancers 2022, 14(1), 217; https://doi.org/10.3390/cancers14010217 - 03 Jan 2022

Cited by 22 | Viewed by 3252

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is still difficult to treat due to insufficient methods for early diagnosis and prediction of therapy response. Furthermore, surveillance after curatively intended surgery lacks adequate methods for timely detection of recurrence. Therefore, several molecules have been analyzed as predictors [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is still difficult to treat due to insufficient methods for early diagnosis and prediction of therapy response. Furthermore, surveillance after curatively intended surgery lacks adequate methods for timely detection of recurrence. Therefore, several molecules have been analyzed as predictors of recurrence or early detection of PDAC. Enhanced understanding of molecular tumorigenesis and treatment response triggered the identification of novel biomarkers as predictors for response to conventional chemotherapy or targeted therapy. In conclusion, progress has been made especially in the prediction of therapy response with biomarkers. The use of molecules for early detection and recurrence of PDAC is still at an early stage, but there are promising approaches in noninvasive biomarkers, composite panels and scores that can already ameliorate the current clinical practice. The present review summarizes the current state of research on biomarkers for diagnosis and therapy of pancreatic cancer. Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

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15 pages, 2245 KiB

Open AccessReview

Intrahepatic Cholangiocarcinoma: A Summative Review of Biomarkers and Targeted Therapies

by Alexandra W. Acher, Alessandro Paro, Ahmed Elfadaly, Diamantis Tsilimigras and Timothy M. Pawlik

Cancers 2021, 13(20), 5169; https://doi.org/10.3390/cancers13205169 - 15 Oct 2021

Cited by 20 | Viewed by 2414

Abstract

Although rare, intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy and the incidence of ICC has increased 14% per year in recent decades. Treatment of ICC remains difficult as most people present with advanced disease not amenable to curative-intent surgical [...] Read more.

Although rare, intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy and the incidence of ICC has increased 14% per year in recent decades. Treatment of ICC remains difficult as most people present with advanced disease not amenable to curative-intent surgical resection. Even among patients with operable disease, margin-negative surgical resection can be difficult to achieve and the incidence of recurrence remains high. As such, there has been considerable interest in systemic chemotherapy and targeted therapy for ICC. Over the last decade, the understanding of the molecular and genetic foundations of ICC has reshaped treatment approaches and strategies. Next-generation sequencing has revealed that most ICC tumors have at least one targetable mutation. These advancements have led to multiple clinical trials to examine the safety and efficacy of novel therapeutics that target tumor-specific molecular and genetic aberrations. While these advancements have demonstrated survival benefit in early phase clinical trials, continued investigation in randomized larger-scale trials is needed to further define the potential clinical impact of such therapy. Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

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Other

Jump to: Research, Review

3 pages, 223 KiB

Open AccessReply

Reply to Lissing et al. Comment on “Ramai et al. Risk of Hepatocellular Carcinoma in Patients with Porphyria: A Systematic Review. Cancers 2022, 14, 2947”

by Daryl Ramai, Smit S. Deliwala, Saurabh Chandan, Janice Lester, Jameel Singh, Jayanta Samanta, Sara di Nunzio, Fabio Perversi, Francesca Cappellini, Aashni Shah, Michele Ghidini, Rodolfo Sacco, Antonio Facciorusso and Luca Giacomelli

Cancers 2023, 15(4), 1187; https://doi.org/10.3390/cancers15041187 - 13 Feb 2023

Cited by 1 | Viewed by 1009

Abstract

We thank Dr. Lissing and colleagues for providing us with these helpful comments [...] Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

6 pages, 221 KiB

Open AccessComment

Comment on Ramai et al. Risk of Hepatocellular Carcinoma in Patients with Porphyria: A Systematic Review. Cancers 2022, 14, 2947

by Mattias Lissing, Daphne Vassiliou, Pauline Harper, Eliane Sardh and Staffan Wahlin

Cancers 2023, 15(3), 795; https://doi.org/10.3390/cancers15030795 - 28 Jan 2023

Cited by 1 | Viewed by 1093

Abstract

We read with interest this review by Ramai et al. [...] Full article

(This article belongs to the Special Issue Hepatobiliary and Pancreatic Neoplasms: Biomarkers and Targeted Therapy)

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