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Diagnosis, Molecular Pathogenesis, and Targeted Therapies for Cholangiocarcinoma
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Diagnosis, Molecular Pathogenesis, and Targeted Therapies for Cholangiocarcinoma

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Gastroenterology & Hepatopancreatobiliary Medicine".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 15745

Special Issue Editor

Prof. Dr. Diego F. Calvisi

E-Mail Website
Guest Editor
Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany
Interests: liver cancer; hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; mouse models; cancer genetics and epigenetics; signal transduction; cancer metabolism; precision medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Cholangiocarcinoma (CCA) is a highly lethal disease with few therapeutic options and rising incidence. The prognosis is generally poor, mainly due to the diagnosis of the disease at an advanced, inoperable stage. Thus, early markers of CCA should be identified and characterized for rapid detection and surgical removal of the tumor. Nonetheless, even when the tumor can be completely resected, often patients experience recurrence. Therefore, novel and effective therapies (possibly individualized) are urgently needed to significantly improve the prognosis of CCA patients. For this purpose, a deeper understanding of the molecular mechanisms involved in CCA development and progression is imperative. Over the last few years, the histopathological alterations ultimately leading to progressed CCA have been better defined. In addition, the landscape of genetic and epigenetic alterations associated with cholangiocarcinogenesis has been unraveled due to the improvement in the transcriptomic and sequencing methodologies. However, this advancement in the knowledge of CCA has not been successfully translated into curative therapies for CCA to date, although encouraging results are coming from preclinical and clinical studies.

Considering the importance of CCA in the field of medicine and research, the journal Journal of Clinical Medicine is launching this Special Issue.

We deeply encourage you and your co-workers to submit your articles reporting on this important topic. Reviews or original articles dealing with the biochemical and molecular aspects associated with CCA diagnosis, molecular pathogenesis, and targeted therapies in the preclinical (experimental) and clinical setting are welcome.

Prof. Dr. Diego F. Calvisi
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 short 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. Journal of Clinical Medicine 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 2600 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

  • cholangiocarcinoma
  • precision medicine
  • molecular mechanisms
  • signal transduction
  • histopathology

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Published Papers (4 papers)

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10 pages, 932 KiB  
Article
Uses of Inflammatory Markers for Differentiation of Intrahepatic Mass-Forming Cholangiocarcinoma from Liver Abscess: Case-Control Study
by Sun Chul Lee, Sun Ju Kim, Min Heui Yu, Kyong Joo Lee and Yong Sung Cha
J. Clin. Med. 2020, 9(10), 3194; https://doi.org/10.3390/jcm9103194 - 1 Oct 2020
Cited by 3 | Viewed by 2151
Abstract
Background: Pyogenic liver abscess (LA) is difficult to distinguish from intrahepatic mass-forming cholangiocarcinoma (IMCC) in the emergency department (ED). We evaluated the predictive ability of white blood cells (WBC) and C-reactive protein (CRP) levels, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio [...] Read more.
Background: Pyogenic liver abscess (LA) is difficult to distinguish from intrahepatic mass-forming cholangiocarcinoma (IMCC) in the emergency department (ED). We evaluated the predictive ability of white blood cells (WBC) and C-reactive protein (CRP) levels, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and delta neutrophil index (DNI) in LA and IMCC in the ED. Methods: Forty patients with IMCC between January 2011 and December 2018 were included in this study. For each patient with IMCC, two control patients with LA were enrolled based on matching age and sex,—i.e., 80 patients with LA. Results: Inflammatory markers, including WBC, PLR, NLR, DNI, and CRP were significantly higher in the LA group than in the IMCC group. For both groups, the area under the curve (AUC) of the initial CRP value was significantly higher (AUC: 0.909) than that of the initial serum WBC count, PLR, and DNI levels. On multivariable logistic regression analysis with inflammatory markers, serum CRP (odds ratio, 1.290; 95% confidence interval, 1.148–1.449, p < 0.001) was the only significant predictor for differentiation between the LA and IMCC groups. Conclusion: Serum CRP may be a potential inflammatory marker to differentiate IMCC from LA in the ED. Full article
(This article belongs to the Special Issue Diagnosis, Molecular Pathogenesis, and Targeted Therapies for Cholangiocarcinoma)
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18 pages, 2151 KiB  
Article
Molecular Profiling in Daily Clinical Practice: Practicalities in Advanced Cholangiocarcinoma and Other Biliary Tract Cancers
by Angela Lamarca, Zainul Kapacee, Michael Breeze, Christopher Bell, Dean Belcher, Helen Staiger, Claire Taylor, Mairéad G. McNamara, Richard A. Hubner and Juan W. Valle
J. Clin. Med. 2020, 9(9), 2854; https://doi.org/10.3390/jcm9092854 - 3 Sep 2020
Cited by 74 | Viewed by 5440
Abstract
Background: Molecular profiling is becoming increasingly relevant in the management of patients with advanced cancer; to identify targetable aberrations and prognostic markers to enable a precision medicine strategy. Methods: Eligible patients were those diagnosed with advanced biliary tract cancer (BTC) including intrahepatic (iCCA) [...] Read more.
Background: Molecular profiling is becoming increasingly relevant in the management of patients with advanced cancer; to identify targetable aberrations and prognostic markers to enable a precision medicine strategy. Methods: Eligible patients were those diagnosed with advanced biliary tract cancer (BTC) including intrahepatic (iCCA) and extrahepatic cholangiocarcinoma (eCCA), gallbladder cancer (GBC), and ampullary carcinoma (Amp) who underwent molecular profiling between April 2017 and June 2020 based on analysis of either tumour samples (FoundationOne CDx®/Oncomine® platforms) or ctDNA (FoundationOne Liquid® platform (Foundation Medicine, Cambridge, MA, USA)). Baseline patient characteristics and molecular profiling outcomes were extracted. The primary aim was to describe sample failure rate. Secondary aims included description of reason for sample failure, summary of findings derived from molecular profiling, and assessment of concordance between paired tissue and ctDNA samples. Results: A total of 149 samples from 104 individual patients diagnosed with advanced BTC were identified and eligible for this analysis: 68.2% iCCA, 100% advanced stage; 94.2% received palliative therapy. The rate of sample failure was 26.8% for tissue and 15.4% for ctDNA; p-value 0.220, predominantly due to insufficient (defined as <20%) tumour content in the sample (the reason for 91.2% of tissue sample failure). Of the 112 samples successfully analysed, pathological molecular findings were identified in the majority of samples (88.4%) and identification of pathological findings using ctDNA, was possible regardless of whether the patient was on active treatment at time of blood acquisition or not (p-value 1.0). The rate of targetable alterations identified was 40.2% across all successfully-analysed samples (39 iCCA; 6 non-iCCA): IDH1 mutations (19.1% of individual patients), FGFR2 alterations (10.1% and 5.6% of individual patients had FGFR2 fusions and mutations, respectively); 10.6% of all patients (12.4% of patients with successfully analysed samples) entered trials with matched targeted therapies as a consequence. Concordance of findings for paired tissue and paired tissue-ctDNA was high (3/3; 100% and 6/6; 100%, respectively). Twelve ctDNA samples were taken prior to palliative treatment initiation, median maximum mutant allele frequency (MAF) was 0.47 (range 0.21–19.8); no significant association between reported maximum MAF and progression-free survival (PFS) or overall survival (OS) (all Cox regression p-values > 0.273). A total of 15 patients (16.6%) harboured alterations in DNA damage repair (DDR) genes; when treated with platinum-based chemotherapy, there was a trend towards increased partial response rate (21.4% vs. 15.9%; p-value 0.653), radiological benefit rate (64.3% vs. 36.2%; p-value 0.071), and longer OS (median OS 20.4 months (95% CI 7.9–26.7) vs. 13.3 (95 CI 11.0–16.4); Cox Regression HR 0.79 (95% CI 0.39–1.61), p-value 0.527). Conclusions: Molecular profiling is of use for identification of novel therapeutic strategies for patients with advanced BTC (mainly iCCA). One in four archived tissue samples may have insufficient tumour content for molecular profiling; ctDNA-based approaches may overcome these obstacles. Full article
(This article belongs to the Special Issue Diagnosis, Molecular Pathogenesis, and Targeted Therapies for Cholangiocarcinoma)
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Review

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15 pages, 411 KiB  
Review
The Role of Surgical Resection and Liver Transplantation for the Treatment of Intrahepatic Cholangiocarcinoma
by Guergana Panayotova, Jarot Guerra, James V. Guarrera and Keri E. Lunsford
J. Clin. Med. 2021, 10(11), 2428; https://doi.org/10.3390/jcm10112428 - 30 May 2021
Cited by 6 | Viewed by 3559
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a rare and complex malignancy of the biliary epithelium. Due to its silent presentation, patients are frequently diagnosed late in their disease course, resulting in poor overall survival. Advances in molecular profiling and targeted therapies have improved medical management, [...] Read more.
Intrahepatic cholangiocarcinoma (iCCA) is a rare and complex malignancy of the biliary epithelium. Due to its silent presentation, patients are frequently diagnosed late in their disease course, resulting in poor overall survival. Advances in molecular profiling and targeted therapies have improved medical management, but long-term survival is rarely seen with medical therapy alone. Surgical resection offers a survival advantage, but negative oncologic margins are difficult to achieve, recurrence rates are high, and the need for adequate future liver remnant limits the extent of resection. Advances in neoadjuvant and adjuvant treatments have broadened patient treatment options, and these agents are undergoing active investigation, especially in the setting of advanced, initially unresectable disease. For those who are not able to undergo resection, liver transplantation is emerging as a potential curative therapy in certain cases. Patient selection, favorable tumor biology, and a protocolized, multidisciplinary approach are ultimately necessary for best patient outcomes. This review will discuss the current surgical management of locally advanced, liver-limited intrahepatic cholangiocarcinoma as well as the role of liver transplantation for select patients with background liver disease. Full article
(This article belongs to the Special Issue Diagnosis, Molecular Pathogenesis, and Targeted Therapies for Cholangiocarcinoma)
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27 pages, 1973 KiB  
Review
ErBb Family Proteins in Cholangiocarcinoma and Clinical Implications
by Wook Jin
J. Clin. Med. 2020, 9(7), 2255; https://doi.org/10.3390/jcm9072255 - 16 Jul 2020
Cited by 17 | Viewed by 4015
Abstract
The erythroblastic leukemia viral oncogene homolog (ErBb) family consists of the receptor tyrosine kinases (RTK) epidermal growth factor receptor (EGFR; also called ERBB1), ERBB2, ERBB3, and ERBB4. This family is closely associated with the progression of cholangiocarcinoma (CC) through the regulation of cellular [...] Read more.
The erythroblastic leukemia viral oncogene homolog (ErBb) family consists of the receptor tyrosine kinases (RTK) epidermal growth factor receptor (EGFR; also called ERBB1), ERBB2, ERBB3, and ERBB4. This family is closely associated with the progression of cholangiocarcinoma (CC) through the regulation of cellular networks, which are enhanced during tumorigenesis, metastasis, and chemoresistance. Additionally, the constitutive activation of cellular signaling by the overexpression and somatic mutation-mediated alterations conferred by the ErBb family on cholangiocarcinoma and other cancers enhances tumor aggressiveness and chemoresistance by contributing to the tumor microenvironment. This review summarizes the recent findings on the molecular functions of the ErBb family and their mutations during the progression of cholangiocarcinoma. It also discusses the developments and applications of various devising strategies for targeting the ErBb family through different inhibitors in various stages of clinical trials, which are essential for improving targeted clinical therapies. Full article
(This article belongs to the Special Issue Diagnosis, Molecular Pathogenesis, and Targeted Therapies for Cholangiocarcinoma)
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