Research

15 pages, 1090 KiB

Open AccessArticle

Population-Attributable Fractions of Personal Comorbidities for Liver, Gallbladder, and Bile Duct Cancers

by Kari Hemminki, Kristina Sundquist, Jan Sundquist, Asta Försti, Vaclav Liska, Akseli Hemminki and Xinjun Li

Cancers 2023, 15(12), 3092; https://doi.org/10.3390/cancers15123092 - 07 Jun 2023

Cited by 2 | Viewed by 1335

Abstract

Background: We aim to estimate population-attributable fractions (PAF) for 13 comorbidities potentially predisposing to hepatobiliary cancer of hepatocellular carcinoma (HCC), gallbladder cancer (GBC), cancers of the intrahepatic and extrahepatic bile ducts (ICC and ECC), and ampullary cancer. Methods: Patients were identified from the [...] Read more.

Background: We aim to estimate population-attributable fractions (PAF) for 13 comorbidities potentially predisposing to hepatobiliary cancer of hepatocellular carcinoma (HCC), gallbladder cancer (GBC), cancers of the intrahepatic and extrahepatic bile ducts (ICC and ECC), and ampullary cancer. Methods: Patients were identified from the Swedish Inpatient Register from 1987 to 2018 and cancers from the Swedish Cancer Registry from 1997 through 2018. PAFs were calculated for each comorbidity-associated cancer using a cohort study design. Results: For male HCC, the major individual comorbidities (PAF > 10) were diabetes, alcohol-related liver disease, and hepatitis C virus infection. For female HCC, diabetes and autoimmune diseases were important contributors. For female GBC, gallstone disease was an overwhelming contributor, with a PAF of 30.57%, which was also important for men. The overall PAF for male ICC was almost two times higher than the female one. For ECC and ampullary cancer, infection of bile ducts was associated with the highest PAF. Conclusions: The 13 comorbidities accounted for 50% or more of the potential etiological pathways of each hepatobiliary cancer except female ICC. The underlying convergent mechanism for these cancers may be chronic inflammation lasting for decades and thus offering possibilities for intervention and disease monitoring. Full article

(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment)

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13 pages, 555 KiB

Open AccessArticle

Prognostic Value of Erythroblastic Leukemia Viral Oncogene Homolog 2 and Neuregulin 4 in Hepatocellular Carcinoma

by Woo Sun Rou, Hyuk Soo Eun, Sorim Choung, Hong Jae Jeon, Jong Seok Joo, Sun Hyung Kang, Eaum Seok Lee, Seok Hyun Kim, In Sun Kwon, Bon Jeong Ku and Byung Seok Lee

Cancers 2023, 15(9), 2634; https://doi.org/10.3390/cancers15092634 - 06 May 2023

Cited by 1 | Viewed by 1349

Abstract

Although the roles of erythroblastic leukemia viral oncogene homolog 2 (ERBB2), neuregulin 4 (NRG4), and mitogen-inducible gene 6 (MIG6) in epidermal growth factor receptor signaling in hepatocellular carcinoma (HCC) and other malignancies have been previously investigated, the prognostic value of their serum levels [...] Read more.

Although the roles of erythroblastic leukemia viral oncogene homolog 2 (ERBB2), neuregulin 4 (NRG4), and mitogen-inducible gene 6 (MIG6) in epidermal growth factor receptor signaling in hepatocellular carcinoma (HCC) and other malignancies have been previously investigated, the prognostic value of their serum levels in HCC remains undetermined. In the present study, correlations between serum levels and tumor characteristics, overall survival, and tumor recurrence were analyzed. Furthermore, the prognostic potential of the serum levels of these biomarkers was evaluated relative to that of alpha-fetoprotein. Both ERBB2 and NRG4 correlated with the Barcelona Clinic Liver Cancer stage, ERBB2 correlated with the tumor-maximal diameter, and NRG4 correlated with a tumor number. Cox proportional hazards regression analysis revealed that ERBB2 (hazard ratio [HR], 2.719; p = 0.007) was an independent prognostic factor for overall survival. Furthermore, ERBB2 (HR, 2.338; p = 0.002) and NRG4 (HR, 431.763; p = 0.001) were independent prognostic factors for tumor recurrence. The products of ERBB2 and NRG4 had a better area under the curve than alpha-fetoprotein for predicting 6-month, 1-year, 3-year, and 5-year mortality. Therefore, these factors could be used to evaluate prognosis and monitor treatment response in patients with HCC. Full article

(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment)

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9 pages, 1118 KiB

Open AccessArticle

Real World Data for Pancreatic Adenocarcinoma from a Population-Based Study in France

by Bogdan Badic, Marie Morvan, Lucille Quénéhervé, Servane Bouzeloc, Tiphaine Kermarrec, Jean-Baptiste Nousbaum and Noémi Reboux

Cancers 2023, 15(2), 525; https://doi.org/10.3390/cancers15020525 - 15 Jan 2023

Viewed by 1644

Abstract

Pancreatic cancer is associated with high mortality rates, and most cases are diagnosed at advanced stages. This study aimed to evaluate the prognostic factors for survival in pancreatic adenocarcinoma. Data from the Finistere registry of digestive database were used in this analysis. This [...] Read more.

Pancreatic cancer is associated with high mortality rates, and most cases are diagnosed at advanced stages. This study aimed to evaluate the prognostic factors for survival in pancreatic adenocarcinoma. Data from the Finistere registry of digestive database were used in this analysis. This retrospective population-based study included 2117 patients with pancreatic adenocarcinoma diagnosed between 2005 and 2019. Cox regression was used to assess the impact of different prognostic factors. The overall median age was 74 (IQR 65.0–81.0). The majority of pancreatic adenocarcinoma 1120 (52.90%) occurred in the head of the pancreas. The type of surgical resection correlated with age (pancreaticoduodenectomy performed in 13.39% of patients aged under 65 years and only 1.49% of patients aged ≥ 80 years). For the entire cohort, 1-year mortality rate after diagnosis was 77.81%. Chemotherapy was associated with better survival for both operated (HR 0.17 95% CI 0.22; 0.64 p < 0.001) and unoperated patients (HR 0.41 95% CI 0.27; 0.61 p < 0.001). Palliative radiotherapy was associated with improved survival (HR 0.69 95% CI 0.56; 0.85 p < 0.001). Among operated patients, the presence of lung metastases (median 34.06; CI 20.06; 34.66) was associated with better survival compared with liver metastases (median 21.10; CI 18.10; 28.96), peritoneal carcinomatosis (median 11.00; CI 8.53; 14.63), or distant metastases (median 15.16; CI 12.66; 18.13) (p = 0.0001). Age, curative surgery, positive lymph nodes, chemotherapy, and palliative radiotherapy were corelated with overall survival. Surgical resection is the only potentially curative treatment, but less than a quarter of patients were eligible. Full article

(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment)

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14 pages, 2522 KiB

Open AccessArticle

Expression of MUC16/CA125 Is Associated with Impaired Survival in Patients with Surgically Resected Cholangiocarcinoma

by Maximilian N. Kinzler, Falko Schulze, Steffen Gretser, Nada Abedin, Jörg Trojan, Stefan Zeuzem, Andreas A. Schnitzbauer, Dirk Walter, Peter J. Wild and Katrin Bankov

Cancers 2022, 14(19), 4703; https://doi.org/10.3390/cancers14194703 - 27 Sep 2022

Cited by 2 | Viewed by 1740

Abstract

MUC16/CA125 is associated with cancer proliferation in several tumor entities. The data on MUC16 expression in cholangiocarcinoma (CCA) tissue are very limited. The aim of this study was to assess the MUC16 status and its impact on survival in CCA patients. All the [...] Read more.

MUC16/CA125 is associated with cancer proliferation in several tumor entities. The data on MUC16 expression in cholangiocarcinoma (CCA) tissue are very limited. The aim of this study was to assess the MUC16 status and its impact on survival in CCA patients. All the patients with surgically resected CCA that were diagnosed between August 2005 and December 2021 at the University Hospital Frankfurt were retrospectively analyzed. A 7-Mucin biomarker panel was assessed by immunohistochemistry. For overall survival (OS), Kaplan–Meier curves and Cox-regression analyses were performed. Randomly selected intrahepatic cholangiocarcinoma (iCCA) were further processed for differential expression profiling. A total of 168 patients with CCA were classified as MUC16 (−) (66%, n = 111) and MUC16 (+) (34%, n = 57). Subgroup analyses revealed a median OS of 56.1 months (95% CI = 42.4–69.9 months) and 27.4 months (95% CI = 15.8–39.1 months) for MUC16 (−) and MUC16 (+), respectively (p < 0.001). In multivariate analysis, MUC16 (+) (HR = 1.6, 95% CI = 1–2.6, p = 0.032) was an independent risk factor for poor prognosis. Prominently deregulated pathways have been identified following MUC16 expression, overrepresented in cell cycle and immune system exhaustion processes. These findings suggest including MUC16 in clinical routine diagnostics as well as studying its molecular pathways to identify further mechanistic key players. Full article

(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment)

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Review

Jump to: Research, Other

21 pages, 7324 KiB

Open AccessReview

Current Trends in Surgical Management of Hepatocellular Carcinoma

by Isabella Angeli-Pahim, Anastasia Chambers, Sergio Duarte and Ali Zarrinpar

Cancers 2023, 15(22), 5378; https://doi.org/10.3390/cancers15225378 - 12 Nov 2023

Cited by 2 | Viewed by 1329

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Surgical management, including hepatic resection, liver transplantation, and ablation, offers the greatest potential for a curative approach. This review aims to discuss recent advancements in HCC surgery and identify unresolved issues in [...] Read more.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Surgical management, including hepatic resection, liver transplantation, and ablation, offers the greatest potential for a curative approach. This review aims to discuss recent advancements in HCC surgery and identify unresolved issues in the field. Treatment selection relies on the BCLC staging system, with surgical therapies primarily recommended for early-stage disease. Recent studies have shown that patients previously considered unresectable, such as those with portal vein tumor thrombus and uncomplicated portal hypertension, may benefit from hepatic resection. Minimally invasive surgery and improved visualization techniques are also explored, alongside new techniques for optimizing future liver remnant, ex vivo resection, and advancements in hemorrhage control. Liver transplantation criteria, particularly the long-standing Milan criteria, are critically examined. Alternative criteria proposed and tested in specific regions are presented. In the context of organ shortage, bridging therapy plays a critical role in preventing tumor progression and maintaining patients eligible for transplantation. Lastly, we explore emerging ablation modalities, comparing them with the current standard, radiofrequency ablation. In conclusion, this comprehensive review provides insights into recent trends and future prospects in the surgical management of HCC, highlighting areas that require further investigation. Full article

(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment)

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16 pages, 1241 KiB

Open AccessReview

Advances in the Early Detection of Hepatobiliary Cancers

by Hasan Çağrı Yıldırım, Gozde Kavgaci, Elvin Chalabiyev and Omer Dizdar

Cancers 2023, 15(15), 3880; https://doi.org/10.3390/cancers15153880 - 30 Jul 2023

Cited by 1 | Viewed by 1759

Abstract

Hepatocellular cancer (HCC) and biliary tract cancers (BTCs) have poor survival rates and a low likelihood of a cure, especially in advanced-stage disease. Early diagnosis is crucial and can significantly improve survival rates through curative treatment approaches. Current guidelines recommend abdominal ultrasonography (USG) [...] Read more.

Hepatocellular cancer (HCC) and biliary tract cancers (BTCs) have poor survival rates and a low likelihood of a cure, especially in advanced-stage disease. Early diagnosis is crucial and can significantly improve survival rates through curative treatment approaches. Current guidelines recommend abdominal ultrasonography (USG) and alpha-fetoprotein (AFP) monitoring for HCC screening in high-risk groups, and abdominal USG, magnetic resonance imaging (MRI), and magnetic resonance cholangiopancreatography (MRCP) monitoring for biliary tract cancer. However, despite this screening strategy, many high-risk individuals still develop advanced-stage HCC and BTC. Blood-based biomarkers are being developed for use in HCC or BTC high-risk groups. Studies on AFP, AFP-L3, des-gamma-carboxy prothrombin, glypican-3 (GPC3), osteopontin (OPN), midkine (MK), neopterin, squamous cell carcinoma antigen (SCCA), Mac-2-binding protein (M2BP), cyclic guanosine monophosphate (cGMP), and interleukin-6 biomarkers for HCC screening have shown promising results when evaluated individually or in combination. In the case of BTCs, the potential applications of circulating tumor DNA, circulating microRNA, and circulating tumor cells in diagnosis are also promising. These biomarkers have shown potential in detecting BTCs in early stages, which can significantly improve patient outcomes. Additionally, these biomarkers hold promise for monitoring disease progression and evaluating response to therapy in BTC patients. However, further research is necessary to fully understand the clinical utility of these biomarkers in the diagnosis and management of HCC and BTCs. Full article

(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment)

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26 pages, 3463 KiB

Open AccessReview

Immunotherapy in Biliary Tract Cancers: Current Standard-of-Care and Emerging Strategies

by Justin H. Lo, Rajiv Agarwal, Laura W. Goff and Thatcher R. Heumann

Cancers 2023, 15(13), 3312; https://doi.org/10.3390/cancers15133312 - 23 Jun 2023

Cited by 8 | Viewed by 2849

Abstract

Biliary tract cancers (BTCs), comprising intrahepatic, perihilar, and distal cholangiocarcinoma as well as gallbladder adenocarcinoma, continue to be challenging to manage. Conventional chemotherapy regimens for advanced disease are limited in both options and benefits, and more effective perioperative regimens are also needed. Over [...] Read more.

Biliary tract cancers (BTCs), comprising intrahepatic, perihilar, and distal cholangiocarcinoma as well as gallbladder adenocarcinoma, continue to be challenging to manage. Conventional chemotherapy regimens for advanced disease are limited in both options and benefits, and more effective perioperative regimens are also needed. Over the last decade, immunotherapy has had a profound impact on the management of many solid tumor types, particularly in using immune checkpoint inhibition to enable a tumor-directed T cell response. Immunotherapy administered on its own has had limited utility in BTCs, in part due to a hostile immune microenvironment and the relative infrequency of biomarker-based tumor-agnostic indications for immunotherapy. However, immunotherapy in conjunction with chemotherapy, molecularly targeted therapies, and/or anti-angiogenic therapies has gained traction, supported by evidence that these agents can impart favorable immunomodulatory effects on the tumor microenvironment. The TOPAZ-1 trial led to the first BTC-specific immunotherapy approval, establishing the combination of durvalumab with gemcitabine and cisplatin as the preferred first-line treatment for advanced or metastatic disease. Recently, the KEYNOTE-966 trial showed positive results for the combination of pembrolizumab with gemcitabine and cisplatin in the same setting, adding further evidence for the addition of immune checkpoint inhibition to the standard chemotherapy backbone. Meanwhile, advances in the molecular profiling of BTCs has contributed to the recent proliferation of molecularly targeted therapeutics for the subset of BTCs harboring alterations in IDH1, FGFR2, MAP kinase signaling, HER2, and beyond, and there has been great interest in investigating combinations of these agents with immunotherapy. Emerging immunotherapy strategies beyond immune checkpoint inhibition are also being studied in BTCs, and these include immunostimulatory receptor agonists, Wnt signaling modulators, adoptive cell therapy, and cancer vaccines. A large number of trials are underway to explore promising new combinations and immune-targeted strategies, offering opportunities to expand the role of immunotherapy in BTC management in the near future. Full article

(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment)

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12 pages, 272 KiB

Open AccessEditor’s ChoiceReview

The Role of HER2 Status in the Biliary Tract Cancers

by Ruveyda Ayasun, Muhammet Ozer and Ilyas Sahin

Cancers 2023, 15(9), 2628; https://doi.org/10.3390/cancers15092628 - 05 May 2023

Cited by 5 | Viewed by 2800

Abstract

Despite recent advances, biliary tract cancer (BTC) is traditionally known as being hard to treat with a poor prognosis. Recent state-of-the-art genomic technologies such as next-generation sequencing (NGS) revolutionized cancer management and shed light on the genomic landscape of BTCs. There are ongoing [...] Read more.

Despite recent advances, biliary tract cancer (BTC) is traditionally known as being hard to treat with a poor prognosis. Recent state-of-the-art genomic technologies such as next-generation sequencing (NGS) revolutionized cancer management and shed light on the genomic landscape of BTCs. There are ongoing clinical trials to assess the efficacy of HER2-blocking antibodies or drug conjugates in BTCs with HER2 amplifications. However, HER2 amplifications may not be the sole eligibility factor for these clinical trials. In this review, we aimed to comprehensively examine the role of somatic HER2 alterations and amplifications in patient stratification and provide an overview of the current state of ongoing clinical trials. Full article

(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment)

21 pages, 668 KiB

Open AccessReview

A Comprehensive Narrative Review on the History, Current Landscape, and Future Directions of Hepatocellular Carcinoma (HCC) Systemic Therapy

by Alexander Lazzaro and Kevan L. Hartshorn

Cancers 2023, 15(9), 2506; https://doi.org/10.3390/cancers15092506 - 27 Apr 2023

Cited by 4 | Viewed by 1902

Abstract

We provide a comprehensive review of current approved systemic treatment strategies for advanced hepatocellular carcinoma (HCC), starting with the phase III clinical trial of sorafenib which was the first to definitively show a survival benefit. After this trial, there was an initial period [...] Read more.

We provide a comprehensive review of current approved systemic treatment strategies for advanced hepatocellular carcinoma (HCC), starting with the phase III clinical trial of sorafenib which was the first to definitively show a survival benefit. After this trial, there was an initial period of little progress. However, in recent years, an explosion of new agents and combinations of agents has resulted in a markedly improved outlook for patients. We then provide the authors’ current approach to therapy, i.e., “How We Treat HCC”. Promising future directions and important gaps in therapy that persist are finally reviewed. HCC is a highly prevalent cancer worldwide and the incidence is growing due not only to alcoholism, hepatitis B and C, but also to steatohepatitis. HCC, like renal cell carcinoma and melanoma, is a cancer largely resistant to chemotherapy but the advent of anti-angiogenic, targeted and immune therapies have improved survival for all of these cancers. We hope this review will heighten interest in the field of HCC therapies, provide a clear outline of the current data and strategy for treatment, and sensitize readers to new developments that are likely to emerge in the near future. Full article

(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment)

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Other

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11 pages, 605 KiB

Open AccessSystematic Review

Outcomes of Transarterial Embolisation (TAE) vs. Transarterial Chemoembolisation (TACE) for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

by Alexander Lawson, Sivesh K. Kamarajah, Alessandro Parente, Kamil Pufal, Ramanivas Sundareyan, Timothy M. Pawlik, Yuk Ting Ma, Tahir Shah, Salil Kharkhanis and Bobby V. M. Dasari

Cancers 2023, 15(12), 3166; https://doi.org/10.3390/cancers15123166 - 13 Jun 2023

Viewed by 1402

Abstract

Although hepatocellular carcinoma is increasingly common, debate exists surrounding the management of patients with unresectable disease comparing transarterial embolisation (TAE) or transarterial chemoembolisation (TACE). This study aimed to compare the outcomes of patients receiving TAE and TACE. A systematic review was performed using [...] Read more.

Although hepatocellular carcinoma is increasingly common, debate exists surrounding the management of patients with unresectable disease comparing transarterial embolisation (TAE) or transarterial chemoembolisation (TACE). This study aimed to compare the outcomes of patients receiving TAE and TACE. A systematic review was performed using PubMed, Medline, Embase, and Cochrane databases to identify randomised controlled trials (RCTs) until August 2021. The primary outcome was overall survival (OS) and the secondary outcomes were progression-free survival (PFS) and adverse events. Five studies with 609 patients were included in the analysis. There was no statistically significant difference in the OS (p = 0.36) and PFS (p = 0.81). There was no difference in OS among patients treated with a single TACE/TAE versus repeat treatments. Post-procedural adverse effects were higher in the TACE group but were not statistically significant. TACE has comparable long-term survival and complications profile to TAE for patients with HCC. However, the low-to-moderate quality of current RCTs warrants high-quality RCTs are necessary to provide enough evidence to give a definitive answer and inform treatment plans for the future. Full article

(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment)

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12 pages, 692 KiB

Open AccessCommentary

Adoptive Cell Therapy in Hepatocellular Carcinoma: A Review of Clinical Trials

by Muhammet Ozer, Suleyman Yasin Goksu, Baran Akagunduz, Andrew George and Ilyas Sahin

Cancers 2023, 15(6), 1808; https://doi.org/10.3390/cancers15061808 - 16 Mar 2023

Cited by 7 | Viewed by 2035

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Immune checkpoint inhibitors (ICIs) have become the new reference standard in first-line HCC treatment, replacing tyrosine kinase inhibitors (TKIs) such as sorafenib. Many clinical trials with different combinations are already in [...] Read more.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Immune checkpoint inhibitors (ICIs) have become the new reference standard in first-line HCC treatment, replacing tyrosine kinase inhibitors (TKIs) such as sorafenib. Many clinical trials with different combinations are already in development to validate novel immunotherapies for the treatment of patients with HCC. Adoptive cell therapy (ACT), also known as cellular immunotherapy, with chimeric antigen receptors (CAR) or gene-modified T cells expressing novel T cell receptors (TCR) may represent a promising alternative approach to modify the immune system to recognize tumor cells with better clinical outcomes. In this review, we briefly discuss the overview of ACT as a promising treatment modality in HCC, along with recent updates of ongoing clinical trials. Full article

(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment)

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