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12 pages, 2278 KiB

Open AccessArticle

Proposal of a New Definition of “Very Early” Intrahepatic Cholangiocarcinoma—A Retrospective Single-Center Analysis

by Oliver Beetz, Angelica Timrott, Clara A. Weigle, Andreas Schroeter, Sebastian Cammann, Juergen Klempnauer, Florian W. R. Vondran and Felix Oldhafer

J. Clin. Med. 2021, 10(18), 4073; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10184073 - 9 Sep 2021

Cited by 4 | Viewed by 1524

Abstract

Intrahepatic cholangiocarcinoma (ICC) is a rare disease with poor outcome, despite advances in surgical and non-surgical treatment. Recently, studies have reported a favorable long-term outcome of “very early” ICC (based on tumor size and absence of extrahepatic disease) after hepatic resection and liver [...] Read more.

Intrahepatic cholangiocarcinoma (ICC) is a rare disease with poor outcome, despite advances in surgical and non-surgical treatment. Recently, studies have reported a favorable long-term outcome of “very early” ICC (based on tumor size and absence of extrahepatic disease) after hepatic resection and liver transplantation, respectively. However, the prognostic value of tumor size and a reliable definition of early disease remain a matter of debate. Patients undergoing resection of histologically confirmed ICC between February 1996 and January 2021 at our institution were reviewed for postoperative morbidity, mortality, and long-term outcome after being retrospectively assigned to two groups: “very early” (single tumor ≤ 3 cm) and “advanced” ICC (size > 3 cm, multifocality or extrahepatic disease). A total of 297 patients were included, with a median follow-up of 22.8 (0.1–301.7) months. Twenty-one (7.1%) patients underwent resection of “very early” ICC. Despite the small tumor size, major hepatectomies (defined as resection of ≥3 segments) were performed in 14 (66.7%) cases. Histopathological analyses revealed lymph node metastases in 5 (23.8%) patients. Patients displayed excellent postoperative outcome compared to patients with “advanced” disease: intrahospital mortality was not observed, and patients displayed superior long-term survival, with a 5-year survival rate of 58.2% (versus 24.3%) and a median postoperative survival of 62.1 months (versus 25.3 months; p = 0.013). In conclusion, although the concept of a “very early” ICC based solely on tumor size is vague as it does not necessarily reflect an aggressive tumor biology, our proposed definition could serve as a basis for further studies evaluating the efficiency of either surgical resection or liver transplantation for this malignant disease. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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17 pages, 1072 KiB

Open AccessArticle

Liver Resection for Intrahepatic Cholangiocarcinoma—Single-Center Experience with 286 Patients Undergoing Surgical Exploration over a Thirteen Year Period

by Hauke Lang, Janine Baumgart, Stefan Heinrich, Tobias Huber, Lisa-Katharina Heuft, Rabea Margies, Jens Mittler, Felix Hahn, Tiemo S. Gerber, Friedrich Foerster, Arndt Weinmann, Jens U. Marquardt, Roman Kloeckner, Beate K. Straub and Fabian Bartsch

J. Clin. Med. 2021, 10(16), 3559; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10163559 - 13 Aug 2021

Cited by 8 | Viewed by 2293

Abstract

Background: Intrahepatic cholangiocarcinoma (iCCA) accounts for about 10% of primary liver cancer. Surgery is the only potentially curative treatment. We report on our current series of 229 consecutive hepatic resections for iCCA, which is one of the largest Western single-center series published so [...] Read more.

Background: Intrahepatic cholangiocarcinoma (iCCA) accounts for about 10% of primary liver cancer. Surgery is the only potentially curative treatment. We report on our current series of 229 consecutive hepatic resections for iCCA, which is one of the largest Western single-center series published so far. Methods: Between January 2008 to December 2020, a total of 286 patients underwent 307 surgical explorations for intended liver resection of iCCA at our department. Data were analyzed with regard to (1) preoperative treatment of tumor, (2) operative details, (3) perioperative morbidity and mortality, (4) histopathology, (5) outcome measured by tumor recurrence, treatment of recurrence and survival and (6) prognostic factors for overall and disease-free survival. Results: the resectability rate was 74.6% (229/307). In total, 202 primary liver resections, 21 repeated, 5 re-repeated, and 1 re-re-repeated liver resections were performed. In primary liver resections there were 77% (155/202) major hepatectomies. In 39/202 (20%) of patients additional hepatic wedge resections and in 87/202 (43%) patients additional 119 other surgical procedures were performed next to hepatectomy. Surgical radicality in first liver resections was 166 R0-, 33 R1- and 1 R2-resection. Following the first liver resection, the calculated 1-, 3- and 5-year-survival is 80%, 39%, and 22% with a median survival of 25.8 months. Until the completion of data acquisition, tumors recurred in 123/202 (60.9%) patients after a median of 7.5 months (range 1–87.2 months) after resection. A multivariate cox regression revealed tumor size (p < 0.001), T stage (p < 0.001) and N stage (p = 0.003) as independent predictors for overall survival. N stage (p = 0.040), preoperative therapy (p = 0.005), T stage (p = 0.004), tumor size (p = 0.002) and M stage (p = 0.001) were independent predictors for recurrence-free survival. Conclusions: For complete surgical removal, often extended liver resection in combination with complex vascular or biliary reconstruction is required. However, despite aggressive surgery, tumor recurrence is frequent and long-term oncological results are poor. This indicated that surgery alone is unlikely to make great strides in improving prognosis of patients with iCCA, instead clearly suggesting that liver resection should be incorporated in multimodal treatment concepts. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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11 pages, 1527 KiB

Open AccessArticle

The Role of Conventional and Stereotactic Microwave Ablation for Intrahepatic Cholangiocarcinoma

by Corina Kim-Fuchs, Daniel Candinas and Anja Lachenmayer

J. Clin. Med. 2021, 10(13), 2963; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10132963 - 1 Jul 2021

Cited by 7 | Viewed by 2263

Abstract

Background: The incidence and mortality of intrahepatic cholangiocarcinoma (ICCA) is increasing worldwide and curative treatment options are limited due to the aggressive tumor biology and often late diagnosis. Resection of the primary tumor remains the only curative therapy available, as the benefit of [...] Read more.

Background: The incidence and mortality of intrahepatic cholangiocarcinoma (ICCA) is increasing worldwide and curative treatment options are limited due to the aggressive tumor biology and often late diagnosis. Resection of the primary tumor remains the only curative therapy available, as the benefit of palliative chemotherapy and radiotherapy is relatively small. In contrast to hepatocellular carcinoma, minimal-invasive thermal tumor ablation, and in particular stereotactic tumor ablation for small primary cancers or metastases, is not established and data are scarce. Methods: We conducted a literature review in the field of ICCA ablation and retrospective analysis of 10 patients treated by stereotactic microwave ablation (SMWA) for either primary ICCA or liver metastases of ICCA. Results: While current guidelines have no consensus for ablation of primary ICCA, some state that it might be an option in inoperable patients or those with recurrent disease. The literature review revealed 11 studies on microwave ablation for ICCA reporting that MWA for ICCA ≤ 5 cm might be safe and could be a treatment option for patients who are not candidates for surgery. No data has been published on stereotactic microwave ablation (SMWA) for ICCA. The analyses of our own data of 10 patients treated by SMWA for primary ICCA (n = 5) or recurrent ICCA (n = 5) show that the treatment is safe and efficient with short hospital stays and low complication rates. Conclusion: Although thermal ablation, and in particular SMWA, might be a minimally invasive and tissue-sparing curative treatment alternative for small ICCA in the diseased liver and ICCA metastases, the oncologic benefit still needs to be shown in larger studies with longer follow-up. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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21 pages, 1786 KiB

Open AccessArticle

Compelling Long-Term Results for Liver Resection in Early Cholangiocarcinoma

by Jan Bednarsch, Zoltan Czigany, Lara R. Heij, Dong Liu, Marcel den Dulk, Georg Wiltberger, Philipp Bruners, Tom Florian Ulmer, Ulf Peter Neumann and Sven Arke Lang

J. Clin. Med. 2021, 10(13), 2959; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10132959 - 30 Jun 2021

Cited by 7 | Viewed by 1908

Abstract

Surgery for intrahepatic cholangiocarcinoma (iCCA) is associated with a high rate of recurrence even after complete resection. To achieve acceptable results, preoperative patient selection is crucial. Hence, we aimed to identify preoperative characteristics with prognostic value focusing on certain radiological features. Patients who [...] Read more.

Surgery for intrahepatic cholangiocarcinoma (iCCA) is associated with a high rate of recurrence even after complete resection. To achieve acceptable results, preoperative patient selection is crucial. Hence, we aimed to identify preoperative characteristics with prognostic value focusing on certain radiological features. Patients who underwent hepatectomy for iCCA between 2010 and 2020 at University Hospital, RWTH Aachen were included. Kaplan–Meier and Cox regressions were applied for survival analysis and associations of overall survival (OS) and recurrence-free survival (RFS) with clinical/radiological characteristics, respectively. Based on radiological features patients were stratified into three groups: single nodule ≤ 3 cm, single nodule > 3 cm, and ≥2 nodules. Analysis of 139 patients revealed a mean OS of 142 months for those with a single nodule ≤3 cm, median OS of 28 months with a single nodule >3 cm, and 19 months with ≥2 nodules, respectively. Multivariable analyses based on preoperative characteristics showed the radiological stratification to be independently associated with OS (HR (hazard ratio) = 4.25 (1 nodule, >3 cm), HR = 5.97 (≥2 nodules), p = 0.011), RFS (HR = 4.18 (1 nodule, >3 cm), and HR = 11.07 (≥2 nodules), p = 0.001). In conclusion, patients with single iCCA ≤3 cm show compelling OS and RFS. Basic radiological features (e.g., nodule size, number) are prognostic for patients undergoing surgery and useful in preoperative patient selection. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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12 pages, 636 KiB

Open AccessArticle

Laparoscopic Surgery for Intrahepatic Cholangiocarcinoma: A Focus on Oncological Outcomes

by Francesca Ratti, Andrea Casadei-Gardini, Federica Cipriani, Guido Fiorentini, Federica Pedica, Valentina Burgio, Stefano Cascinu and Luca Aldrighetti

J. Clin. Med. 2021, 10(13), 2828; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10132828 - 26 Jun 2021

Cited by 17 | Viewed by 1730

Abstract

Background: The aim of the present study was to analyze the long-term outcomes of laparoscopic and open surgery for intrahepatic cholangiocarcinoma (iCCA) in a series, collected in a tertiary referral center with a high annual volume of laparoscopic activity. Methods: Between January 2004 [...] Read more.

Background: The aim of the present study was to analyze the long-term outcomes of laparoscopic and open surgery for intrahepatic cholangiocarcinoma (iCCA) in a series, collected in a tertiary referral center with a high annual volume of laparoscopic activity. Methods: Between January 2004 and June 2020, 446 liver resections (LR) were performed for iCCA: of these, 179 were performed by laparoscopic surgery (LS) and 267 with the open approach. The two groups were matched through a 1:1 propensity score using covariates representative of patient and disease characteristics. The study and control groups were compared, with specific attention given to oncological outcomes (rate of R0, depth of resection margins, overall and disease-free survival, rate, and site of recurrence). Results: The number of retrieved nodes, rate, and depth of negative resection margins were comparable between the two groups. The interval time between surgery and subsequent adjuvant treatments was significantly shorter in LS patients. No differences were shown even in the comparison between the LS and the open group in terms of median disease-free and overall survival. Moreover, the disease recurrence rate was comparable between the LS and the open groups (45.2% versus 56.7%), and the recurrence pattern was similar. Conclusions: The minimally invasive approach for iCCA was once again confirmed to be associated with advantages in terms of intraoperative and short-term outcomes, but was also proven to be oncologically non-inferior to the open counterpart. In the present study, overall and disease-free survival were found to be similar between the two approaches. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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13 pages, 994 KiB

Open AccessArticle

Recurrence after Curative Resection for Intrahepatic Cholangiocarcinoma: How to Predict the Chance of Repeat Hepatectomy?

by Serena Langella, Nadia Russolillo, Paolo Ossola, Andrea-Pierre Luzzi, Michele Casella, Roberto Lo Tesoriere and Alessandro Ferrero

J. Clin. Med. 2021, 10(13), 2820; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10132820 - 26 Jun 2021

Cited by 8 | Viewed by 2028

Abstract

(1) Background: Tumor recurrence after liver resection (LR) for intrahepatic cholangiocarcinoma (ICC) is common. Repeat liver resection (RLR) for recurrent ICC results in good survival outcomes in selected patients. The aim of this study was to investigate factors affecting the chance of resectability [...] Read more.

(1) Background: Tumor recurrence after liver resection (LR) for intrahepatic cholangiocarcinoma (ICC) is common. Repeat liver resection (RLR) for recurrent ICC results in good survival outcomes in selected patients. The aim of this study was to investigate factors affecting the chance of resectability of recurrent ICC. (2) Methods: LR for ICC performed between January 2001 and December 2020 were retrospectively reviewed. Patients who had undergone first LR were considered for the study. Data on recurrences were analyzed. A logistic regression model was used for multivariable analysis of factors related to RLR rate. (3) Results: In total, 140 patients underwent LR for ICC. Major/extended hepatectomies were required in 105 (75%) cases. The 90-day mortality was 5.7%, Clavien–Dindo grade 3, 4 complications were 9.3%, N+ disease was observed in 32.5%, and the median OS was 38.3 months. Recurrence occurred in 91 patients (65%). The site of relapse was the liver in 53 patients (58.2%). RLR was performed in 21 (39.6%) patients. Factors that negatively affected RLR were time to recurrence ≤12 months (OR 7.4, 95% CI 1.68–33.16, p = 0.008) and major hepatectomy (OR 16.7, 95% CI 3.8–73.78, p < 0.001) at first treatment. Survival after recurrence was better in patients who underwent RLR as compared with not resected patients (31 vs. 13.2 months, p = 0.02). (4) Conclusions: Patients with ICC treated at first resection with major hepatectomy and those who recurred in ≤12 months had significantly lower probability to receive a second resection for recurrence. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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10 pages, 4104 KiB

Open AccessArticle

Clinicopathological Significance of Syndecan-1 in Cholangiocarcinoma: A Study Based on Immunohistochemistry and Public Sequencing Data

by Tiemo S. Gerber, Fabian Bartsch, Daniel C. Wagner, Mario Schindeldecker, Lisa-Katharina Heuft, Wilfried Roth, Hauke Lang and Beate K. Straub

J. Clin. Med. 2021, 10(13), 2745; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10132745 - 22 Jun 2021

Cited by 5 | Viewed by 1759

Abstract

Background: Syndecan-1 (CD138; SDC1) is a heparan sulfate proteoglycan that has been attributed a key role in cancer progression in ductal adenocarcinoma of the pancreas. We therefore aimed to investigate the role of syndecan-1 in cholangiocarcinoma. Methods: We analyzed syndecan-1 expression in [...] Read more.

Background: Syndecan-1 (CD138; SDC1) is a heparan sulfate proteoglycan that has been attributed a key role in cancer progression in ductal adenocarcinoma of the pancreas. We therefore aimed to investigate the role of syndecan-1 in cholangiocarcinoma. Methods: We analyzed syndecan-1 expression in a large, clinicopathologically well-characterized collective of 154 intrahepatic cholangiocarcinoma, 221 extrahepatic cholangiocarcinomas, and 95 gallbladder carcinomas as well as respective normal tissues and precursor lesions by immunohistochemistry with digital image analysis and correlated with recurrence-free survival and prognostic markers. Furthermore, we conducted an analysis of cancer genes in the cholangiocarcinoma cohort of The Cancer Genome Atlas (TCGA). Results: During cholangiocarcinogenesis, syndecan-1-expression decreased when compared to normal bile ducts and biliary intraepithelial neoplasia; however, syndecan-1 levels were found to be elevated in lymph node metastases. In the TCGA cohort, high mRNA SDC1 levels were associated with poor prognosis in intrahepatic cholangiocarcinoma. However, in our large cohort, the immunohistochemical syndecan-1 expression did not significantly correlate with recurrence-free survival. Conclusions: Syndecan-1 was found to be downregulated during cholangiocarcinogenesis, yet we could not show significant effects on prognosis on protein level. Further analyses are needed to further depict its specific role. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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12 pages, 1214 KiB

Open AccessArticle

The Addition of Transarterial Chemoembolization to Palliative Chemotherapy Extends Survival in Intrahepatic Cholangiocarcinoma

by Simon Johannes Gairing, Felix Thol, Lukas Müller, Felix Hahn, Thomas Thomaidis, Carolin Czauderna, Fabian Bartsch, Michael Bernhard Pitton, Jens Uwe Marquardt, Marcus-Alexander Wörns, Peter Robert Galle, Markus Moehler, Arndt Weinmann, Roman Kloeckner and Friedrich Foerster

J. Clin. Med. 2021, 10(12), 2732; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10122732 - 21 Jun 2021

Cited by 8 | Viewed by 2152

Abstract

Incidence and mortality of intrahepatic cholangiocarcinoma (iCCA) have been increasing continuously. Recent studies suggest that the combination of palliative chemotherapy (pCTX) and transarterial chemoembolization (TACE) improves overall survival (OS). This study aimed to evaluate the outcome of patients treated with TACE and pCTX [...] Read more.

Incidence and mortality of intrahepatic cholangiocarcinoma (iCCA) have been increasing continuously. Recent studies suggest that the combination of palliative chemotherapy (pCTX) and transarterial chemoembolization (TACE) improves overall survival (OS). This study aimed to evaluate the outcome of patients treated with TACE and pCTX in unresectable iCCA at our tertiary care center. A group of 14 patients was treated with both pCTX and TACE. The non-randomized control group of 59 patients received pCTX alone. Patients received a median of two pCTX lines in both groups. Those treated with TACE underwent a median number of 3.5 sessions. Median OS from the time of unresectability was 26.2 months in the pCTX + TACE group versus 13.1 months in the pCTX group (p = 0.008). Controlling for albumin, bilirubin, ECOG (Eastern Cooperative Oncology Group) performance status, and UICC (Union for International Cancer Control) stage, the addition of TACE still conferred an OS benefit of 12.95 months (p = 0.014). A propensity score matching analysis yielded an OS benefit of 14 months from the time of unresectability for the pCTX + TACE group (p = 0.020). The addition of TACE to pCTX may provide an OS benefit for patients with unresectable iCCA. Thus, patients with liver-dominant iCCA undergoing standard-of-care pCTX should be considered for additional treatment with TACE. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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11 pages, 1560 KiB

Open AccessArticle

Influence of Lymphangio (L), Vascular (V), and Perineural (Pn) Invasion on Recurrence and Survival of Resected Intrahepatic Cholangiocarcinoma

by Fabian Bartsch, Lisa-Katharina Heuft, Janine Baumgart, Maria Hoppe-Lotichius, Rabea Margies, Tiemo S. Gerber, Friedrich Foerster, Arndt Weinmann, Beate K. Straub, Jens Mittler, Stefan Heinrich and Hauke Lang

J. Clin. Med. 2021, 10(11), 2426; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10112426 - 30 May 2021

Cited by 8 | Viewed by 2159

Abstract

(1) Background: Intrahepatic cholangiocarcinoma (ICC) is a rare malignancy. Besides tumor, nodal, and metastatic status, the UICC TNM classification describes further parameters such as lymphangio- (L0/L1), vascular (V0/V1/V2), and perineural invasion (Pn0/Pn1). The aim of this study was to analyze the influence of [...] Read more.

(1) Background: Intrahepatic cholangiocarcinoma (ICC) is a rare malignancy. Besides tumor, nodal, and metastatic status, the UICC TNM classification describes further parameters such as lymphangio- (L0/L1), vascular (V0/V1/V2), and perineural invasion (Pn0/Pn1). The aim of this study was to analyze the influence of these parameters on recurrence and survival. (2) Methods: All surgical explorations for patients with ICC between January 2008 and June 2018 were collected and further analyzed in our institutional database. Statistical analyses focused on perineural, lymphangio-, and vascular invasion examined histologically and their influence on tumor recurrence and survival. (3) Results: Of 210 patients who underwent surgical exploration, 150 underwent curative-intended resection. Perineural invasion was present in 41, lymphangioinvasion in 21, and vascular invasion in 37 patients (V1 n = 34, V2 n = 3). Presence of P1, V+ and L1 was significantly associated with positivity of each other of these factors (p < 0.001, each). None of the three parameters showed direct influence on tumor recurrence in general, but perineural invasion influenced extrahepatic recurrence significantly (p = 0.019). Whereas lymphangio and vascular invasion was neither associated with overall nor recurrence-free survival, perineural invasion was significantly associated with a poor 1-, 3- and 5-year overall survival (OS) of 80%, 35%, and 23% for Pn0 versus 75%, 23%, and 0% for Pn1 (p = 0.027). Concerning recurrence-free survival (RFS), Pn0 showed a 1-, 3- and 5-year RFS of 42%, 18%, and 16% versus 28%, 11%, and 0% for Pn1, but no significance was reached (p = 0.091). (4) Conclusions: Whereas lymphangio- and vascular invasion showed no significant influence in several analyses, the presence of perineural invasion was associated with a significantly higher risk of extrahepatic tumor recurrence and worse overall survival. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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23 pages, 3646 KiB

Open AccessArticle

Prognostic Role of Immune Checkpoint Regulators in Cholangiocarcinoma: A Pilot Study

by Lu Cao, Prashanth Prithviraj, Ritu Shrestha, Revati Sharma, Matthew Anaka, Kim R. Bridle, George Kannourakis, Darrell H.G. Crawford and Aparna Jayachandran

J. Clin. Med. 2021, 10(10), 2191; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10102191 - 19 May 2021

Cited by 11 | Viewed by 3000

Abstract

Cholangiocarcinoma (CCA) is a hepatobiliary malignancy associated with steadily increasing incidence and poor prognosis. Ongoing clinical trials are assessing the effectiveness and safety of a few immune checkpoint inhibitors (ICIs) in CCA patients. However, these ICI treatments as monotherapies may be effective for [...] Read more.

Cholangiocarcinoma (CCA) is a hepatobiliary malignancy associated with steadily increasing incidence and poor prognosis. Ongoing clinical trials are assessing the effectiveness and safety of a few immune checkpoint inhibitors (ICIs) in CCA patients. However, these ICI treatments as monotherapies may be effective for a proportion of patients with CCA. The prevalence and distribution of other immune checkpoints (ICs) in CCA remain unclear. In this pilot study, we screened databases of CCA patients for the expression of 19 ICs and assessed the prognostic significance of these ICs in CCA patients. Notably, expression of immune modulator IDO1 and PD-L1 were linked with poor overall survival, while FASLG and NT5E were related to both worse overall survival and progression-free survival. We also identified immune modulators IDO1, FASLG, CD80, HAVCR2, NT5E, CTLA-4, LGALS9, VTCN1 and TNFRSF14 that synergized with PD-L1 and correlated with worse patient outcomes. In vitro studies revealed that the expression of ICs was closely linked with aggressive CCA subpopulations, such as cancer stem cells and cells undergoing TGF-β and TNF-α-mediated epithelial-to-mesenchymal transition. These findings suggest that the aforementioned IC molecules may serve as potential prognostic biomarkers and drug targets in CCA patients, leading to lasting and durable treatment outcomes. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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14 pages, 1505 KiB

Open AccessArticle

Survival Prediction in Intrahepatic Cholangiocarcinoma: A Proof of Concept Study Using Artificial Intelligence for Risk Assessment

by Lukas Müller, Aline Mähringer-Kunz, Simon Johannes Gairing, Friedrich Foerster, Arndt Weinmann, Fabian Bartsch, Lisa-Katharina Heuft, Janine Baumgart, Christoph Düber, Felix Hahn and Roman Kloeckner

J. Clin. Med. 2021, 10(10), 2071; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10102071 - 12 May 2021

Cited by 5 | Viewed by 2015

Abstract

Several scoring systems have been devised to objectively predict survival for patients with intrahepatic cholangiocellular carcinoma (ICC) and support treatment stratification, but they have failed external validation. The aim of the present study was to improve prognostication using an artificial intelligence-based approach. We [...] Read more.

Several scoring systems have been devised to objectively predict survival for patients with intrahepatic cholangiocellular carcinoma (ICC) and support treatment stratification, but they have failed external validation. The aim of the present study was to improve prognostication using an artificial intelligence-based approach. We retrospectively identified 417 patients with ICC who were referred to our tertiary care center between 1997 and 2018. Of these, 293 met the inclusion criteria. Established risk factors served as input nodes for an artificial neural network (ANN). We compared the performance of the trained model to the most widely used conventional scoring system, the Fudan score. Predicting 1-year survival, the ANN reached an area under the ROC curve (AUC) of 0.89 for the training set and 0.80 for the validation set. The AUC of the Fudan score was significantly lower in the validation set (0.77, p < 0.001). In the training set, the Fudan score yielded a lower AUC (0.74) without reaching significance (p = 0.24). Thus, ANNs incorporating a multitude of known risk factors can outperform conventional risk scores, which typically consist of a limited number of parameters. In the future, such artificial intelligence-based approaches have the potential to improve treatment stratification when models trained on large multicenter data are openly available. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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12 pages, 1252 KiB

Open AccessArticle

Complex Liver Resections for Intrahepatic Cholangiocarcinoma

by Tim Reese, Gregor Pagel, Bettina A. Bause, York von Rittberg, Kim C. Wagner and Karl J. Oldhafer

J. Clin. Med. 2021, 10(8), 1672; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10081672 - 13 Apr 2021

Cited by 8 | Viewed by 2294

Abstract

The only curative treatment option for intrahepatic cholangiocarcinoma (iCCA) is liver resection. Due to central tumor localization and vascular invasion, complex liver resections play an important role in curative treatment. However, the long-term outcomes after complex liver resection are not known. Methods: A [...] Read more.

The only curative treatment option for intrahepatic cholangiocarcinoma (iCCA) is liver resection. Due to central tumor localization and vascular invasion, complex liver resections play an important role in curative treatment. However, the long-term outcomes after complex liver resection are not known. Methods: A retrospective cohort study was conducted for all patients undergoing liver surgery for iCCA. Complex liver resections included ante situm resections, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) and major liver resection with vascular reconstructions. Results: Forty-nine patients (34%) received complex liver resection, 66 patients (46%) received conventional liver resection and 28 patients (20%) were not resectable during exploration. Preoperative characteristics were not different between the groups, except for Union for International Cancer Control (UICC) stages. The postoperative course for complex liver resections was associated with more complications and perioperative mortality. However, long-term survival was not different between complex and conventional resections. Independent risk factors for survival were R0 resections and UICC stage. Four patients underwent ante situm resection without any mortality. Conclusions: Complex liver resections are justified in selected patients and survival is comparable with conventional liver resections. Survival in iCCA is affected by UICC stage or resections margins and not by the complexity of the case. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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14 pages, 1431 KiB

Open AccessArticle

Therapeutic Outcomes and Prognostic Factors of Unresectable Intrahepatic Cholangiocarcinoma: A Data Mining Analysis

by Tomotake Shirono, Takashi Niizeki, Hideki Iwamoto, Shigeo Shimose, Hiroyuki Suzuki, Takumi Kawaguchi, Naoki Kamachi, Yu Noda, Shusuke Okamura, Masahito Nakano, Ryoko Kuromatu, Hironori Koga and Takuji Torimura

J. Clin. Med. 2021, 10(5), 987; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10050987 - 2 Mar 2021

Cited by 7 | Viewed by 1968

Abstract

Prognosis of patients with intrahepatic cholangiocarcinoma (ICC) is unsatisfactory. Tumor, host, and treatment factors including hepatic arterial infusion chemotherapy (HAIC) are intricately involved in the progression of ICC. We aimed to identify profiles associated with disease control rate (DCR) and the prognosis of [...] Read more.

Prognosis of patients with intrahepatic cholangiocarcinoma (ICC) is unsatisfactory. Tumor, host, and treatment factors including hepatic arterial infusion chemotherapy (HAIC) are intricately involved in the progression of ICC. We aimed to identify profiles associated with disease control rate (DCR) and the prognosis of patients with unresectable ICC by decision tree analysis. We analyzed 31 consecutive patients with unresectable ICC (median age, 71 years; the male ratio was 58.1%). Stage IVB occupied 51.6% of patients, and 38.7% and 58.1% of patients were treated with gemcitabine plus cisplatin combination therapy and HAIC, respectively. Profiles associated with prognosis as well as DCR were investigated by decision tree analysis. The median survival time (MST) of the patients was 11.6 months, and the DCR was 70.9%. Multivariate correlation analysis showed that albumin levels and WBC levels were significantly correlated with survival time (albumin, ρ = 0.3572, p = 0.0485; WBC, ρ = −0.4008, p = 0.0280). In decision tree analysis, WBC level was selected as the initial split variable, and subjects with WBC levels of 6800/μL or less (45.1%) showed a long survival time (MST 476 days). We also demonstrated that the profile associated with the highest DCR was “less than 4.46 mg/dL of CRP levels and treatment with HAIC”. We demonstrated a new prognostic profile for ICC patients, which consisted of WBC and CRP levels. Moreover, we demonstrated that HAIC was associated with better disease control in ICC patients with low CPR levels. Thus, these new profiles may be useful for the management of ICC patients. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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Review

Jump to: Research

11 pages, 286 KiB

Open AccessReview

Image-Guided Local Treatment for Unresectable Intrahepatic Cholangiocarcinoma—Role of Interventional Radiology

by Matthias P. Fabritius, Najib Ben Khaled, Wolfgang G. Kunz, Jens Ricke and Max Seidensticker

J. Clin. Med. 2021, 10(23), 5574; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10235574 - 26 Nov 2021

Cited by 3 | Viewed by 1675

Abstract

Intrahepatic cholangiocarcinoma is a highly aggressive malignancy with an increasing incidence in recent years. Prognosis is poor and most patients are not eligible for resection at the time of initial diagnosis due to the anatomic location, inadequate hepatic reserve, limiting comorbidities or metastatic [...] Read more.

Intrahepatic cholangiocarcinoma is a highly aggressive malignancy with an increasing incidence in recent years. Prognosis is poor and most patients are not eligible for resection at the time of initial diagnosis due to the anatomic location, inadequate hepatic reserve, limiting comorbidities or metastatic disease. Several locoregional therapies from the field of interventional radiology exist for patients who are not amenable for surgery, or in case of local recurrence as a single treatment modality or combined with systemic treatment. To date, evidence is limited, with most conclusions drawn from single-center studies with small patient cohorts, often treated in the salvage situation or for local recurrence after initial resection. Nevertheless, the results are promising and suggest a survival benefit in selected patients. This narrative review focuses on the use of different locoregional treatment options for intrahepatic cholangiocarcinoma. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

9 pages, 264 KiB

Open AccessReview

Vascular Resection for Intrahepatic Cholangiocarcinoma: Current Considerations

by Ruslan Alikhanov, Anna Dudareva, Miguel Ángel Trigo and Alejandro Serrablo

J. Clin. Med. 2021, 10(17), 3829; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10173829 - 26 Aug 2021

Cited by 4 | Viewed by 2352

Abstract

Intrahepatic cholangiocarcinoma (iCCA) accounts for approximately 10% of all primary liver cancers. Surgery is the only potentially curative treatment, even in cases of macrovascular invasion. Since resection offers the only curative chance, even extended liver resection combined with complex vascular or biliary reconstruction [...] Read more.

Intrahepatic cholangiocarcinoma (iCCA) accounts for approximately 10% of all primary liver cancers. Surgery is the only potentially curative treatment, even in cases of macrovascular invasion. Since resection offers the only curative chance, even extended liver resection combined with complex vascular or biliary reconstruction of the surrounding organs seems justified to achieve complete tumour removal. In selected cases, the major vascular resection is the only change to try getting the cure. The best results are achieved by the referral centre with a wide experience in complex liver surgery, such as ALPPS procedure, IVC resection, and ante-situ and ex-situ resections. However, despite aggressive surgery, tumour recurrence occurs frequently and long-term oncological results are very poor. This suggests that significant progress in prognosis cannot be expected by surgery alone. Instead, multimodal treatment including neoadjuvant chemotherapy, radiotherapy, and subsequent adjuvant treatment for iCCA seem to be necessary to improve results. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

13 pages, 1048 KiB

Open AccessReview

Molecular Subtypes and Precision Oncology in Intrahepatic Cholangiocarcinoma

by Carolin Czauderna, Martha M. Kirstein, Hauke C. Tews, Arndt Vogel and Jens U. Marquardt

J. Clin. Med. 2021, 10(13), 2803; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10132803 - 25 Jun 2021

Cited by 14 | Viewed by 3064

Abstract

Cholangiocarcinomas (CCAs) are the second-most common primary liver cancers. CCAs represent a group of highly heterogeneous tumors classified based on anatomical localization into intra- (iCCA) and extrahepatic CCA (eCCA). In contrast to eCCA, the incidence of iCCA is increasing worldwide. Curative treatment strategies [...] Read more.

Cholangiocarcinomas (CCAs) are the second-most common primary liver cancers. CCAs represent a group of highly heterogeneous tumors classified based on anatomical localization into intra- (iCCA) and extrahepatic CCA (eCCA). In contrast to eCCA, the incidence of iCCA is increasing worldwide. Curative treatment strategies for all CCAs involve oncological resection followed by adjuvant chemotherapy in early stages, whereas chemotherapy is administered at advanced stages of disease. Due to late diagnosis, high recurrence rates, and limited treatment options, the prognosis of patients remains poor. Comprehensive molecular characterization has further revealed considerable heterogeneity and distinct prognostic and therapeutic traits for iCCA and eCCA, indicating that specific treatment modalities are required for different subclasses. Several druggable alterations and oncogenic drivers such as fibroblast growth factor receptor 2 gene fusions and hotspot mutations in isocitrate dehydrogenase 1 and 2 mutations have been identified. Specific inhibitors have demonstrated striking antitumor activity in affected subgroups of patients in phase II and III clinical trials. Thus, improved understanding of the molecular complexity has paved the way for precision oncological approaches. Here, we outline current advances in targeted treatments and immunotherapeutic approaches. In addition, we delineate future perspectives for different molecular subclasses that will improve the clinical care of iCCA patients. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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11 pages, 879 KiB

Open AccessReview

Hepatic Arterial Infusion Chemotherapy for Unresectable Intrahepatic Cholangiocarcinoma, a Comprehensive Review

by Marco Massani, Luca Bonariol and Tommaso Stecca

J. Clin. Med. 2021, 10(12), 2552; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10122552 - 9 Jun 2021

Cited by 12 | Viewed by 3604

Abstract

Cholangiocarcinoma (CCA) is the second most common primitive liver cancer. Despite recent advances in the surgical management, the prognosis remains poor, with a 5-year survival rate of less than 5%. Intrahepatic CCA (iCCA) has a median survival between 18 and 30 months, but [...] Read more.

Cholangiocarcinoma (CCA) is the second most common primitive liver cancer. Despite recent advances in the surgical management, the prognosis remains poor, with a 5-year survival rate of less than 5%. Intrahepatic CCA (iCCA) has a median survival between 18 and 30 months, but if deemed unresectable it decreases to 6 months. Most patients have a liver-confined disease that is considered unresectable because of its localization, with infiltration of vascular structures or multifocality. The peculiar dual blood supply allows the delivery of high doses of chemotherapy via a surgically implanted subcutaneous pump, through the predominant arterial tumor vascularization, achieving much higher and more selective tumor drug levels than systemic administration. The results of the latest studies suggest that adequate and early treatment with the combination approach of hepatic arterial infusion (HAI) and systemic (SYS) chemotherapy is associated with improved progression-free and overall survival than SYS or HAI alone for the treatment of unresectable iCCA. Current recommendations are limited by a lack of prospective trials. Individualization of chemotherapy and regimens based on selective targets in mutant iCCA are a focus for future research. In this paper we present a comprehensive review of the studies published to date and ongoing trials. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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15 pages, 737 KiB

Open AccessReview

Management of Intrahepatic Cholangiocarcinoma

by Sudha Kodali, Akshay Shetty, Soumya Shekhar, David W. Victor and Rafik M. Ghobrial

J. Clin. Med. 2021, 10(11), 2368; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10112368 - 27 May 2021

Cited by 16 | Viewed by 8520

Abstract

Cholangiocarcinoma is a tumor that arises as a result of differentiation of the cholangiocytes and can develop from anywhere in the biliary tree. Subtypes of cholangiocarcinoma are differentiated based on their location in the biliary tree. If diagnosed early these can be resected, [...] Read more.

Cholangiocarcinoma is a tumor that arises as a result of differentiation of the cholangiocytes and can develop from anywhere in the biliary tree. Subtypes of cholangiocarcinoma are differentiated based on their location in the biliary tree. If diagnosed early these can be resected, but most cases of intrahepatic cholangiocarcinoma present late in the disease course where surgical resection is not an option. In these patients who are poor candidates for resection, a combination of chemotherapy, locoregional therapies like ablation, transarterial chemo and radioembolization, and in very advanced and metastatic disease, external radiation are the available options. These modalities can improve overall disease-free and progression-free survival chances. In this review, we will discuss the risk factors and clinical presentation of intrahepatic cholangiocarcinoma, diagnosis, available therapeutic options, and future directions for management options. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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17 pages, 1097 KiB

Open AccessReview

Surgical Treatment of Intrahepatic Cholangiocarcinoma: Current and Emerging Principles

by Eliza W. Beal, Jordan M. Cloyd and Timothy M. Pawlik

J. Clin. Med. 2021, 10(1), 104; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10010104 - 30 Dec 2020

Cited by 29 | Viewed by 3853

Abstract

Intrahepatic cholangiocarcinoma (ICC) is a rare, aggressive cancer of the biliary tract. It often presents with locally advanced or metastatic disease, but for patients with early-stage disease, surgical resection with negative margins and portahepatis lymphadenectomy is the standard of care. Recent advancements in [...] Read more.

Intrahepatic cholangiocarcinoma (ICC) is a rare, aggressive cancer of the biliary tract. It often presents with locally advanced or metastatic disease, but for patients with early-stage disease, surgical resection with negative margins and portahepatis lymphadenectomy is the standard of care. Recent advancements in ICC include refinement of staging, improvement in liver-directed therapies, clarification of the role of adjuvant therapy based on new randomized controlled trials, and advances in minimally invasive liver surgery. In addition, improvements in neoadjuvant strategies and surgical techniques have enabled expanded surgical indications and reduced surgical morbidity and mortality. However, recurrence rates remain high and more effective systemic therapies are still necessary to improve recurrence-free and overall survival. In this review, we focus on current and emerging surgical principals for the management of ICC including preoperative evaluation, current indications for surgery, strategies for future liver remnant augmentation, technical principles, and the role of neoadjuvant and adjuvant therapies. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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36 pages, 10922 KiB

Open AccessReview

Intraductal Papillary Neoplasm of Bile Duct: Updated Clinicopathological Characteristics and Molecular and Genetic Alterations

by Yasuni Nakanuma, Katsuhiko Uesaka, Yuko Kakuda, Takashi Sugino, Keiichi Kubota, Toru Furukawa, Yuki Fukumura, Hiroyuki Isayama and Takuro Terada

J. Clin. Med. 2020, 9(12), 3991; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9123991 - 9 Dec 2020

Cited by 55 | Viewed by 9275

Abstract

Intraductal papillary neoplasm of the bile duct (IPNB), a pre-invasive neoplasm of the bile duct, is being established pathologically as a precursor lesion of invasive cholangiocarcinoma (CCA), and at the time of surgical resection, approximately half of IPNBs show stromal invasion (IPNB associated [...] Read more.

Intraductal papillary neoplasm of the bile duct (IPNB), a pre-invasive neoplasm of the bile duct, is being established pathologically as a precursor lesion of invasive cholangiocarcinoma (CCA), and at the time of surgical resection, approximately half of IPNBs show stromal invasion (IPNB associated with invasive carcinoma). IPNB can involve any part of the biliary tree. IPNB shows grossly visible, exophytic growth in a dilated bile duct lumen, with histologically villous/papillary neoplastic epithelia with tubular components covering fine fibrovascular stalks. Interestingly, IPNB can be classified into four subtypes (intestinal, gastric, pancreatobiliary and oncocytic), similar to intraductal papillary mucinous neoplasm of the pancreas (IPMN). IPNBs are classified into low-grade and high-grade based on lining epithelial features. The new subclassification of IPNB into types 1 (low-grade dysplasia and high-grade dysplasia with regular architecture) and 2 (high-grade dysplasia with irregular architecture) proposed by the Japan–Korea pathologist group may be useful in the clinical field. The outcome of post-operative IPNBs is more favorable in type 1 than type 2. Recent genetic studies using next-generation sequencing have demonstrated the existence of several groups of mutations of genes: (i) IPNB showing mutations in KRAS, GNAS and RNF43 belonged to type 1, particularly the intestinal subtype, similar to the mutation patterns of IPMN; (ii) IPNB showing mutations in CTNNB1 and lacking mutations in KRAS, GNAS and RNF43 belonged to the pancreatobiliary subtype but differed from IPMN. IPNB showing mutation of TP53, SMAD4 and PIK3CA might reflect complicated and other features characterizing type 2. The recent recognition of IPNBs may facilitate further clinical and basic studies of CCA with respect to the pre-invasive and early invasive stages. Full article

(This article belongs to the Special Issue Management of Intrahepatic Cholangiocarcinoma)

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