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Soliman N, Connor AA, Saharia A, Kodali S, Elaileh A, Patel K, Semaan S, Basra T, Victor DW, Simon CJ, Cheah YL, Hobeika MJ, Mobley CM, Divatia M, Dhingra S, Schwartz M, Maqsood A, Heyne K, Abdelrahim M, Javle M, Vauthey JN, Gaber AO, Ghobrial RM. Neoadjuvant Multiagent Systemic Therapy Approach to Liver Transplantation for Perihilar Cholangiocarcinoma. Transplant Direct 2025; 11:e1760. [PMID: 39936132 PMCID: PMC11809964 DOI: 10.1097/txd.0000000000001760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 11/12/2024] [Indexed: 02/13/2025] Open
Abstract
Background Perihilar cholangiocarcinoma (phCCA) has excellent outcomes following liver transplantation (LT). Neoadjuvant radiation-based locoregional therapy is standard-of-care. Gemcitabine and cisplatin (gem/cis) combination systemic therapies have improved outcomes in advanced settings, but their efficacy pre-LT has not been studied. Methods We review our experience following neoadjuvant gem/cis alone versus radiation-based approaches. Patients with phCCA undergoing LT at a single center between January 2008 and February 2023 were identified retrospectively. Neoadjuvant therapy was categorized as gem/cis systemic therapy (ST) alone, or any ST and radiotherapy (RT). Outcomes were posttransplant overall survival (OS), recurrence-free survival (RFS), waitlist time, and pathologic tumor response. Results During study period, 27 phCCA patients underwent LT. One patient decompensated with neoadjuvant therapy and was excluded. Median age was 61 y (interquartile range, 53-68 y) and 14 (54%) were male. Of 26 patients, 12 (46%) received ST and 14 (54%) RT. Six RT patients received gem/cis ST. Median waitlist time was 199 d (interquartile range, 98-405 d) and did not differ by neoadjuvant regimen. Explanted tumors were predominantly T1 stage, without lymphovascular invasion or nodal involvement. Neither pathologic features nor percent tumor necrosis differed by regimen. OS probabilities at 1 and 3 y were 84% and 55% for the cohort. There was no significant difference in OS and RFS when stratified by regimen. Conclusions Post-LT OS, RFS, waitlist time, and tumor response were similar in the 2 groups. Patients with phCCA who do not undergo RT may still be considered for LT under appropriate institution-based protocols that adhere to other established criteria.
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Affiliation(s)
- Nadine Soliman
- Faculty of Biology, Medicine, and Health, University of Manchester, Manchester, United Kingdom
| | - Ashton A. Connor
- Department of Surgery, Houston Methodist Hospital, Houston, TX
- Department of Surgery, Weill Cornell Medical College, New York, NY
| | - Ashish Saharia
- Department of Surgery, Houston Methodist Hospital, Houston, TX
- Department of Surgery, Weill Cornell Medical College, New York, NY
| | - Sudha Kodali
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Department of Medicine, Houston Methodist Hospital, Houston, TX
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Ahmed Elaileh
- Department of Surgery, Houston Methodist Hospital, Houston, TX
| | - Khush Patel
- Department of Surgery, Houston Methodist Hospital, Houston, TX
| | - Samar Semaan
- Department of Surgery, Houston Methodist Hospital, Houston, TX
| | - Tamneet Basra
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Department of Medicine, Houston Methodist Hospital, Houston, TX
| | - David W. Victor
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Department of Medicine, Houston Methodist Hospital, Houston, TX
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | | | - Yee Lee Cheah
- Department of Surgery, Houston Methodist Hospital, Houston, TX
| | - Mark J. Hobeika
- Department of Surgery, Houston Methodist Hospital, Houston, TX
- Department of Surgery, Weill Cornell Medical College, New York, NY
| | - Constance M. Mobley
- Department of Surgery, Houston Methodist Hospital, Houston, TX
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Department of Medicine, Houston Methodist Hospital, Houston, TX
| | - Mukul Divatia
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX
| | - Sadhna Dhingra
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX
| | - Mary Schwartz
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX
| | - Anaum Maqsood
- Division of Medical Oncology, Department of Medicine, Houston Methodist Hospital, Houston, TX
| | - Kirk Heyne
- Department of Medicine, Weill Cornell Medical College, New York, NY
- Division of Medical Oncology, Department of Medicine, Houston Methodist Hospital, Houston, TX
| | - Maen Abdelrahim
- Department of Medicine, Weill Cornell Medical College, New York, NY
- Division of Medical Oncology, Department of Medicine, Houston Methodist Hospital, Houston, TX
| | - Milind Javle
- Department of Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - A. Osama Gaber
- Department of Surgery, Houston Methodist Hospital, Houston, TX
- Department of Surgery, Weill Cornell Medical College, New York, NY
| | - R. Mark Ghobrial
- Department of Surgery, Houston Methodist Hospital, Houston, TX
- Department of Surgery, Weill Cornell Medical College, New York, NY
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Wiederkehr HDA, Wiederkehr JC, Da Igreja MR, Ramos EB, Nogara MS, Soffiatti DS, Massutti A, Sasaki VL, Wiederkehr BDA, Valejo IRM, Coelho JCU. LIVER TRANSPLANTATION IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS: A MULTICENTRIC STUDY. ARQUIVOS BRASILEIROS DE CIRURGIA DIGESTIVA : ABCD = BRAZILIAN ARCHIVES OF DIGESTIVE SURGERY 2023; 36:e1769. [PMID: 37851755 PMCID: PMC10578153 DOI: 10.1590/0102-672020230051e1769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Accepted: 08/17/2023] [Indexed: 10/20/2023]
Abstract
BACKGROUND The prevalence of primary sclerosing cholangitis (PSC) in the general population has not yet been clearly established. The management of PSC should focus on delaying the progression of the disease and restraining its complications. The only curative therapy for the disease remains liver transplantation (LT). PSC is currently the fifth most common indication for LT and corresponds to 5% of all LT indications in adults. AIMS Our objective is to evaluate the indications and outcomes of PSC patients undergoing LT in three liver transplantation centers in southern Brazil - Hospital Santa Isabel in Blumenau, Santa Catarina state, and Hospital das Clínicas and Hospital Nossa Senhora das Graças, in Curitiba, Parana state). METHODS This is a longitudinal observational study of patients with PSC who underwent LT in three major Brazilian medical centers. Electronic medical records and study protocols of all patients subjected to LT from January 2011 to December 2021 were retrospectively reviewed. RESULTS Of the 1,362 transplants performed in the three medical centers, 37 were due to PSC. Recurrence of PSC occurred in three patients (8.1%) in 3.0±2.4 years (range, 1-4 years). The 1-year and 5-year survival rates after the first LT were 83.8 and 80.6%, respectively. The 1-year and 5-year graft survival rates were, respectively, 83.8 and 74.8%. CONCLUSIONS Our experience with LT in patients with PSC demonstrated good patient and graft survival results. Most deaths were due to common factors in patients undergoing LT.
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Affiliation(s)
| | - Julio Cesar Wiederkehr
- Universidade Federal do Paraná, University Hospital, Liver Transplant Department, Curitiba (PR), Brazil
- Santa Isabel Hospital, Liver Transplant Department, Blumenau (SC), Brasil
| | | | | | | | | | - Andrew Massutti
- Santa Isabel Hospital, Liver Transplant Department, Blumenau (SC), Brasil
| | - Vivian Laís Sasaki
- Nossa Senhora das Graças Hospital, Liver Transplant Department, Curitiba (PR), Brazil
| | | | | | - Júlio Cezar Uili Coelho
- Universidade Federal do Paraná, University Hospital, Liver Transplant Department, Curitiba (PR), Brazil
- Nossa Senhora das Graças Hospital, Liver Transplant Department, Curitiba (PR), Brazil
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3
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Dueland S, Smedman TM, Syversveen T, Grut H, Hagness M, Line PD. Long-Term Survival, Prognostic Factors, and Selection of Patients With Colorectal Cancer for Liver Transplant: A Nonrandomized Controlled Trial. JAMA Surg 2023; 158:e232932. [PMID: 37494056 PMCID: PMC10372758 DOI: 10.1001/jamasurg.2023.2932] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 05/06/2023] [Indexed: 07/27/2023]
Abstract
IMPORTANCE Liver transplant for colorectal cancer with liver metastases was abandoned in the 1990s due to poor overall survival. From 2006, liver transplant for in nonresectable colorectal liver metastases has been reexamined through different prospective trials. OBJECTIVE To determine predictive factors for transplant long-term survival and cure after liver transplant. DESIGN, SETTING, AND PARTICIPANTS This was a prospective, nonrandomized controlled cohort study derived from different clinical trials on liver transplant for colorectal liver metastases from 2006 to 2020 at Oslo University Hospital. The trials differed in prognostic inclusion criteria, but the design was otherwise identical regarding follow-up scheme to determine disease recurrence, overall survival, and survival after relapse. Final data analysis was performed on December 31, 2021. All patients with colorectal liver metastases from comparable prospective liver transplant studies were included. EXPOSURE Liver transplant. MAIN OUTCOMES AND MEASURES Disease-free survival, overall survival, and survival time after recurrence were determined in all participants. RESULTS A total of 61 patients (median [range] age, 57.8 [28.7-71.1] years; 35 male [57.4%]) underwent liver transplant at Oslo University Hospital. Posttransplant observation time ranged from 16 to 165 months, and no patient was lost to follow-up. Median disease-free period, overall survival, and survival after relapse were 11.8 (95% CI, 9.3-14.2) months, 60.3 (95% CI, 44.3-76.4) months, and 37.1 (95% CI, 4.6-69.5) months, respectively. Negative predictive factors for overall survival included the following: largest tumor size greater than 5.5 cm (median OS, 25.3 months; 95% CI, 15.8-34.8 months; P <.001), progressive disease while receiving chemotherapy (median OS, 39.8 months; 95% CI, 28.8-50.7 months; P = .02), plasma carcinoembryonic antigen values greater than 80 μg/L (median OS, 26.6 months; 95% CI, 22.7-30.6 months; P <.001), liver metabolic tumor volume on positron emission tomography of greater than 70 cm3 (26.6 months; 95% CI, 11.8-41.5 months; P <.001), primary tumor in the ascending colon (17.9 months; 95% CI, 0-37.5 months; P <.001), tumor burden score of 9 or higher (23.3 months; 95% CI, 19.2-27.4 months; P = .02), and 9 or more liver lesions (42.5 months; 95% CI, 17.2-67.8 months; P = .02). An Oslo score of 0 or Fong Clinical Risk Score of 1 yielded 10-year survival of 88.9% and 80.0%, respectively. CONCLUSIONS AND RELEVANCE Results of this nonrandomized controlled trial suggest that selected patients with liver-only metastases and favorable pretransplant prognostic scoring had long-term survival comparable with conventional indications for liver transplant, thus providing a potential curative treatment option in patients otherwise offered only palliative care.
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Affiliation(s)
- Svein Dueland
- Transplant Oncology Research Group, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
- Section for Transplantation Surgery, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Tor Magnus Smedman
- Transplant Oncology Research Group, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
- Department of Oncology, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Trygve Syversveen
- Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway
| | - Harald Grut
- Department of Radiology, Vestre Viken Hospital Trust, Drammen, Norway
| | - Morten Hagness
- Transplant Oncology Research Group, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
- Section for Transplantation Surgery, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Pål-Dag Line
- Transplant Oncology Research Group, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
- Section for Transplantation Surgery, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Shannon AH, Ruff SM, Schenk AD, Washburn K, Pawlik TM. Updates and Expert Opinions on Liver Transplantation for Gastrointestinal Malignancies. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1290. [PMID: 37512101 PMCID: PMC10383519 DOI: 10.3390/medicina59071290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/12/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023]
Abstract
Transplant oncology is a relatively new field in which transplantation is used to treat patients who would otherwise be unresectable. New anticancer treatment paradigms using tumor and transplant immunology and cancer immunogenomics are emerging. In turn, liver transplantation (LT) has become a potential therapy for certain patients with colorectal cancer (CRC) with liver metastasis, hepatocellular (HCC), cholangiocarcinoma (CCA), and metastatic neuroendocrine tumor (NET) of the liver. Although there are established criteria for LT in HCC, evidence regarding LT as a treatment modality for certain gastrointestinal malignancies is still debated. The aim of this review is to highlight updates in the role of LT for certain malignancies, including HCC, metastatic CRC, hilar CCA, and neuroendocrine tumor (NET), as well as contextualize LT use and discuss controversies in transplant oncology.
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Yilmaz S, Carr BI, Akbulut S. Can the Limits of Liver Transplantation Be Expanded in Perihilar Cholangiocarcinoma? J Gastrointest Cancer 2022; 53:1104-1112. [PMID: 34738188 DOI: 10.1007/s12029-021-00735-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2021] [Indexed: 02/07/2023]
Abstract
The most common location of cholangiocarcinomas is the perihilar region with a frequency of 50-70%. Current standard treatment for perihilar cholangiocarcinomas (pCCA) is surgical resection. In cases where resection treatment is possible, the 5-year survival rate is 8-40%. However, using a very strict patient selection, neoadjuvant radiochemotherapy (NRCT), staging laparotomy, and liver transplantation (LT), called "the Mayo protocol," 5-year survivals of up to 70% in pCCA were reported. This treatment protocol clearly requires an intensive workforce and a harmonious multidisciplinary approach. Reoperation and retransplantation rates are high, which is a reflection of the NRCT. Multicenter studies, systemic reviews, and meta-analysis results, comparing both resection and LT in pCCA treatment and evaluating only LT results, pointed to LT with strict patient selection and full compliance with the treatment. The results of centers experienced in LT are better in treating pCCA. According to Mayo clinical data, histopathological diagnosis could not be obtained in half of the patients with pCCA before NRCT was given. This situation can be explained by the necrosis of the tumor due to the effect of NRCT and the fact that the tumor cannot be detected in the explant liver. This situation raises the following questions: did all patients actually have pCCA? Were these good results due to some patients not having pCCA? The 5-year survival rate was worse in patients with a pathological diagnosis than those without a pathological diagnosis. However, interestingly, recurrence rates were statistically similar in both groups. There was no difference in survival between LT and resection in the R0N0 subgroup in de novo pCCA. There are still many issues that need to be addressed and corrected in pCCA, which is one of the most problematic indications for LT. Significant success has been achieved with NRCT, staging laparotomy, and LT in selected patients with pCCA developing on the basis of PSC or early-stage unresectable de novo pCCA. It can be expected that new NRCT modalities will provide better survival by expanding the indications for LT in pCCA.
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Affiliation(s)
- Sezai Yilmaz
- Liver Transplant Institute, Faculty of Medicine, Inonu University, Malatya, 44280, Turkey
| | - Brian I Carr
- Liver Transplant Institute, Faculty of Medicine, Inonu University, Malatya, 44280, Turkey
| | - Sami Akbulut
- Liver Transplant Institute, Faculty of Medicine, Inonu University, Malatya, 44280, Turkey.
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6
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Pery R, Smoot RL, Thiels CA, Cleary SP, Vierkant RA, Ilyas SI, Gores GJ, Nagorney DM. Hepatobiliary and pancreatic resection for cholangiocarcinoma in patients with primary sclerosing cholangitis. Br J Surg 2022; 109:1032-1035. [DOI: 10.1093/bjs/znac229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 04/09/2022] [Accepted: 06/09/2022] [Indexed: 11/14/2022]
Affiliation(s)
- Ron Pery
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic , Rochester, Minnesota , USA
- Department of Surgery and Transplantation, Sheba Medical Center, Tel Hashomer, affiliated with the Faculty of Medicine, Tel Aviv University , Tel Aviv , Israel
| | - Rory L Smoot
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic , Rochester, Minnesota , USA
| | - Cornelius A Thiels
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic , Rochester, Minnesota , USA
| | - Sean P Cleary
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic , Rochester, Minnesota , USA
| | - Robert A Vierkant
- Department of Quantitative Health Sciences, Mayo Clinic , Rochester, Minnesota , USA
| | - Sumera I Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester, Minnesota , USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester, Minnesota , USA
| | - David M Nagorney
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic , Rochester, Minnesota , USA
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7
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Houben P, Schimmack S, Unterrainer C, Döhler B, Mehrabi A, Süsal C. Rare Malignant Indications for Liver Transplantation: A Collaborative Transplant Study Report. Front Surg 2021; 8:678392. [PMID: 34926560 PMCID: PMC8678034 DOI: 10.3389/fsurg.2021.678392] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 10/27/2021] [Indexed: 12/04/2022] Open
Abstract
Introduction: Hepatocellular carcinoma (HCC) is by far the leading malignant indication for liver transplantation (LT). Few other malignancies, including cholangiocellular carcinoma (CCC), metastases from neuroendocrine tumors (NET), and sarcomas of the liver (LSAR), also are commonly accepted indications for LT. However, there is limited information on their outcome after LT. Methods: Graft and patient survival in 14,623 LTs performed in patients with hepatocellular carcinoma, CCC, NET, and LSAR from 1988 to 2017 and reported to the Collaborative Transplant Study were analyzed. Results: The study group consisted of 13,862 patients who had HCC (94.8%), 498 (3.4%) who had CCC, 100 (0.7%) who had NET, and 163 (1.1%) who had LSAR. CCC patients showed a 5-year graft survival rate of 32.1%, strikingly lower than the 63.2% rate in HCC, 51.6% rate in NET, and 64.5% rate in LSAR patients (P < 0.001 for all vs. CCC). Multivariable Cox regression analysis revealed a significantly higher risk of graft loss and death due to cancer during the first five post-transplant years in CCC vs. HCC patients (HR 1.77 and 2.56; P < 0.001 for both). The same risks were increased also in NET and LSAR patients but did not reach statistical significance. Conclusion: Among patients with rare malignant indications for LT, CCC patients showed significantly impaired graft as well as patient survival compared to HCC patients. The observed differences might challenge traditional decision-making processes for LT indication and palliative treatment in specific hepatic malignancies.
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Affiliation(s)
- Philipp Houben
- Department of General, Visceral, and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Simon Schimmack
- Department of General, Visceral, and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Bernd Döhler
- Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral, and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Caner Süsal
- Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany.,Transplant Immunology Research Center of Excellence, Koç Üniversitesi, Istanbul, Turkey
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8
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Cadamuro M, Lasagni A, Lamarca A, Fouassier L, Guido M, Sarcognato S, Gringeri E, Cillo U, Strazzabosco M, Marin JJ, Banales JM, Fabris L. Targeted therapies for extrahepatic cholangiocarcinoma: preclinical and clinical development and prospects for the clinic. Expert Opin Investig Drugs 2021; 30:377-388. [PMID: 33622120 DOI: 10.1080/13543784.2021.1880564] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Until recently, cholangiocarcinoma (CCA) was a largely overlooked disease, and among CCAs, extrahepatic CCA (eCCA) was even more neglected. Despite the growing impact of molecularly targeted therapies and immunotherapy, prognosis of eCCA is dismal. Therefore, unraveling the complex molecular landscape of eCCA has become an urgent need. Deep phenotyping studies have revealed that eCCA is a heterogeneous tumor, harboring specific alterations categorizable into four classes, 'Mesenchymal', 'Proliferation', 'Immune', 'Metabolic'. Molecular alterations convey the activation of several pro-oncogenic pathways, where either actionable drivers or outcome predictors can be identified.Areas covered: We offer insights on perturbed pathways, molecular profiling, and actionable targets in eCCA and present a perspective on the potential stepping-stones to future progress. A systematic literature search in PubMed/ClinicalTrials.gov websites was performed by authors from different disciplines according to their specific topic knowledge to identify the newest and most relevant advances in precision medicine of eCCA.Expert opinion: eCCA is a distinct entity with unique features in terms of molecular classes, oncogenic drivers, and tumor microenvironment. Since more prevalent mutations are currently undruggable, and immunotherapy can be offered only to a minority of patients, international collaborations are instrumental to improve the understanding of the molecular underpins of this disease.
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Affiliation(s)
- Massimiliano Cadamuro
- Department of Molecular Medicine (DMM), University of Padua, Padua. Italy.,International Center for Digestive Health (ICDH), University of Milan-Bicocca, Milan, Italy
| | - Alberto Lasagni
- Division of General Medicine, Padua University-Hospital, Padua, Italy
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation, Manchester, United Kingdom.,Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Laura Fouassier
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Paris, France
| | - Maria Guido
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy.,Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Samantha Sarcognato
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy.,Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Enrico Gringeri
- Hepatobiliary Surgery and Liver Transplantation, Padua University-Hospital, Padua, Italy.,Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, Italy
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation, Padua University-Hospital, Padua, Italy.,Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, Italy
| | - Mario Strazzabosco
- International Center for Digestive Health (ICDH), University of Milan-Bicocca, Milan, Italy.,Digestive Disease Section, Liver Center, Yale University, New Haven, CT, US
| | - Jose Jg Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital -, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastian, Spain
| | - Luca Fabris
- Department of Molecular Medicine (DMM), University of Padua, Padua. Italy.,International Center for Digestive Health (ICDH), University of Milan-Bicocca, Milan, Italy.,Division of General Medicine, Padua University-Hospital, Padua, Italy.,Digestive Disease Section, Liver Center, Yale University, New Haven, CT, US
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9
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Pitchumoni CS, Ravindran N. Biliary Neoplasms. GERIATRIC GASTROENTEROLOGY 2021:1437-1448. [DOI: 10.1007/978-3-030-30192-7_105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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10
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Akateh C, Ejaz AM, Pawlik TM, Cloyd JM. Neoadjuvant treatment strategies for intrahepatic cholangiocarcinoma. World J Hepatol 2020; 12:693-708. [PMID: 33200010 PMCID: PMC7643214 DOI: 10.4254/wjh.v12.i10.693] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 08/21/2020] [Accepted: 09/08/2020] [Indexed: 02/06/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy and is increasing in incidence. Long-term outcomes are optimized when patients undergo margin-negative resection followed by adjuvant chemotherapy. Unfortunately, a significant proportion of patients present with locally advanced, unresectable disease. Furthermore, recurrence rates are high even among patients who undergo surgical resection. The delivery of systemic and/or liver-directed therapies prior to surgery may increase the proportion of patients who are eligible for surgery and reduce recurrence rates by prioritizing early systemic therapy for this aggressive cancer. Nevertheless, the available evidence for neoadjuvant therapy in ICC is currently limited yet recent advances in liver directed therapies, chemotherapy regimens, and targeted therapies have generated increasing interest its role. In this article, we review the rationale for, current evidence for, and ongoing research efforts in the use of neoadjuvant therapy for ICC.
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Affiliation(s)
- Clifford Akateh
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Aslam M Ejaz
- Department of Surgery, The Ohio State University, Columbus, OH 43210, United States
| | - Timothy Michael Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Jordan M Cloyd
- Department of Surgery, The Ohio State University, Columbus, OH 43210, United States
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11
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Machairas N, Kostakis ID, Tsilimigras DI, Prodromidou A, Moris D. Liver transplantation for hilar cholangiocarcinoma: A systematic review. Transplant Rev (Orlando) 2020; 34:100516. [PMID: 31711828 DOI: 10.1016/j.trre.2019.100516] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 10/27/2019] [Accepted: 11/03/2019] [Indexed: 02/07/2023]
Abstract
Patients with hilar cholangiocarcinoma (hCCA) have advanced disease at presentation and therefore curative treatment options are limited. Liver transplantation (LT), in the case of unresectable disease, is theoretically an attractive option, as it offers the maximum resection margin and at the same time removes the underlying parenchymal liver disease. In the past years a number of studies have aimed to evaluate to potential beneficial role of neo adjuvant therapy followed by LT for treating patients with unresectable hCCA. The objective of our systematic review was to collect and evaluate long-term outcomes of patients with hCCA undergoing LT. A systematic search of 4 electronic databases (Medline, Scopus, Google Scholar and ClinicalTrails.gov databases) was performed for articles published between January 2000 and May 2019. A total of 13 studies with 698 patients were finally included in the present systematic review. A proportion of 74.4% of patients received combination of chemotherapy and radiation as a part of neoadjuvant therapy. One-, 3- and 5-year overall survival rates ranged greatly among the included studies from 58% to 92%, 31% to 80% and 20% to 74%, respectively. Recurrence rates ranged from 16% to 61%, whilst perioperative mortality ranged from 0% to 25.5%. LT could provide acceptable long-term outcomes in the setting of neoadjuvant chemoradiation and strict patient selection criteria. Taking into account organ shortage, combined with the lack of level I evidence, more prospective randomized trials are needed in order to establish certain indications, rigorous criteria and standardized protocols for LT in hCCA and provide the maximal potential benefits for these patients.
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Affiliation(s)
- Nikolaos Machairas
- Department of HPB Surgery and Liver Transplantation, Royal Free London, London, United Kingdom
| | - Ioannis D Kostakis
- Department of HPB Surgery and Liver Transplantation, Royal Free London, London, United Kingdom
| | | | | | - Dimitrios Moris
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
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Moris D, Kostakis ID, Machairas N, Prodromidou A, Tsilimigras DI, Ravindra KV, Sudan DL, Knechtle SJ, Barbas AS. Comparison between liver transplantation and resection for hilar cholangiocarcinoma: A systematic review and meta-analysis. PLoS One 2019; 14:e0220527. [PMID: 31365594 PMCID: PMC6668826 DOI: 10.1371/journal.pone.0220527] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Accepted: 07/17/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Hilar cholangiocarcinoma (hCCA) is a rare and aggressive malignancy with R0 resection being currently the only option for long-term survival. With the improvement in the outcomes of liver transplantation (LT), the indications for LT have expanded to include other malignant tumors, such as hCCA. The aim of the present analysis is to demonstrate and critically evaluate the outcomes of LT compared to resection with curative intent in patients with hCCA. METHODS We systematically searched the literature for articles published up to May 2018. The following algorithm was applied ((hilar cholangiocarcinoma) OR (perihilar cholangiocarcinoma) OR klatskin$ OR (bile duct neoplasm) OR cholangiocarcinoma) AND (transplant$ OR graft$). RESULTS Neoadjuvant treatment with chemotherapy and radiation therapy was far more common in the LT group, with very few patients having received preoperative therapy in the resection group (p = 0.0005). Moreover, length of hospital stay was shorter after LT than after resection (p<0.00001). In contrast, no difference was found between the two treatment methods concerning postoperative mortality (p = 0.57). There was a trend towards longer overall survival after LT in comparison with resection. This was not obvious in the first year postoperatively, however, the advantage of LT over resection became obvious at 3 years after the operation (p = 0.02). CONCLUSIONS In non-disseminated unresectable tumors, LT seems to have a non-inferior survival. In the same patients, neoadjuvant chemoradiotherapy and/or strict selection criteria may contribute to superior survival outcomes compared to curative-intent resection. Due to the scarcity of level 1 evidence, it remains unclear whether LT should be increasingly considered for technically resectable early stage hCCA.
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Affiliation(s)
- Dimitrios Moris
- Department of Surgery, Duke University Medical Center, Durham, NC, United States of America
| | - Ioannis D. Kostakis
- Department of Transplantation, Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Nikolaos Machairas
- Third Department of Surgery, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Anastasia Prodromidou
- Third Department of Surgery, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Diamantis I. Tsilimigras
- Third Department of Surgery, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Kadiyala V. Ravindra
- Department of Surgery, Duke University Medical Center, Durham, NC, United States of America
| | - Debra L. Sudan
- Department of Surgery, Duke University Medical Center, Durham, NC, United States of America
| | - Stuart J. Knechtle
- Department of Surgery, Duke University Medical Center, Durham, NC, United States of America
| | - Andrew S. Barbas
- Department of Surgery, Duke University Medical Center, Durham, NC, United States of America
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Recent advances in liver transplantation for cancer: The future of transplant oncology. JHEP Rep 2019; 1:377-391. [PMID: 32039389 PMCID: PMC7005652 DOI: 10.1016/j.jhepr.2019.07.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 07/15/2019] [Accepted: 07/16/2019] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation is widely indicated as a curative treatment for selected patients with hepatocellular carcinoma. However, with recent therapeutic advances, as well as efforts to increase the donor pool, liver transplantation has been carefully expanded to patients with other primary or secondary malignancies in the liver. Cholangiocarcinoma, colorectal and neuroendocrine liver metastases, and hepatic epithelioid haemangioendothelioma are amongst the most relevant new indications. In this review we discuss the fundamental concepts of this ambitious undertaking, as well as the newest indications for liver transplantation, with a special focus on future perspectives within the recently established concept of transplant oncology.
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Dondorf F, Uteβ F, Fahrner R, Felgendreff P, Ardelt M, Tautenhahn HM, Settmacher U, Rauchfuβ F. Liver Transplant for Perihilar Cholangiocarcinoma (Klatskin Tumor): The Essential Role of Patient Selection. EXP CLIN TRANSPLANT 2019; 17:363-369. [PMID: 29911960 DOI: 10.6002/ect.2018.0024] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVES Perihilar cholangiocarcinoma (Klatskin tumor) is a rare tumor entity, which is diagnosed late due to uncharacteristic symptoms. The therapeutic strategy for cure is still liver resection. Liver transplant in cases of locally irresectable tumors represents an alternative potential curative therapy for a select group of patients. MATERIALS AND METHODS We present our data of 22 patients with irresectable Klatskin tumors who received transplants between 1996 and 2015. We analyzed relevant prognostic factors for the selection of patients to be transplanted to ensure an acceptable overall survival and reviewed known and established selection criteria. RESULTS Four factors (age, tumor size, serum level of carbohydrate antigen 19-9, percutaneous transhepatic cholangiodrainage) could be detected for possible patient selection. Positive lymph node status and advanced tumor stage according to the Union for International Cancer Control were confirmed as negative prognostic factors for survival after transplant. CONCLUSIONS Liver transplant is a curative therapy for selected patients with irresectable Klatskin tumors, but further prospective studies are urgently needed.
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Affiliation(s)
- Felix Dondorf
- From the Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany
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15
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[Frontiers in liver transplantation in indication and techniques]. Chirurg 2018; 90:102-109. [PMID: 30413847 DOI: 10.1007/s00104-018-0761-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
BACKGROUND The frontiers in liver transplantation are intrinsically expansions of indications, e.g. hepatocellular carcinoma and (perihilar) cholangiocarcinoma, recipients with more severe concomitant diagnoses or "soft" contraindications and technically demanding reconstruction procedures of vascular structures (for portal vein thrombosis or aorto-hepatic conduits). In addition, an extension of the donor pool with suboptimal donor organs (old donors and steatotic livers) is of interest. METHODS This article presents the current situation based on personal experiences in daily practice and an appropriate literature review. RESULTS A significant reduction of 1‑year patient survival has been reported in Germany. The percentage of so-called marginal donor organs is inversely proportional to the very low donation rate and parallel to the waiting list mortality. Simultaneously, the proportion of inpatients with multiple organ failure is rising. CONCLUSION Results-oriented and controlled liver transplantation currently prohibits making inroads into the previously intrinsic frontiers. As long as the current circumstances do not change, a shift in the intrinsic frontiers of that which is surgically feasible will not be possible. The current situation forces the transplant surgeon to apply a more restrictive indications and organ acceptance policy. With this approach we can try to regain the previously excellent short- and long-term results of a 1‑year survival of 90% and a 20-year survival of 50%.
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16
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Mittler J, Heinrich S, Lang H. [Indications for transplantation and bridging procedures for primary hepatobiliary malignancies]. Chirurg 2018; 89:865-871. [PMID: 30238348 DOI: 10.1007/s00104-018-0733-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Primary hepatobiliary malignancies are hepatocellular carcinoma, cholangiocarcinoma and the rare hepatocellular cholangiocarcinoma (mixed tumor). The indications for liver transplantation and the oncological prognosis differ considerably between these tumor entities. Treatment and decision making for these tumors are often complicated by an underlying chronic liver disease. The aim of this review is to delineate the indications for transplantation and bridging therapies for each cancer entity as well as to highlight some aspects pertinent to transplantation, such as the principles of organ allocation.
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Affiliation(s)
- J Mittler
- Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Universitätsmedizin Mainz, Langenbeckstraße 1, 55131, Mainz, Deutschland.
| | - S Heinrich
- Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Universitätsmedizin Mainz, Langenbeckstraße 1, 55131, Mainz, Deutschland
| | - H Lang
- Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Universitätsmedizin Mainz, Langenbeckstraße 1, 55131, Mainz, Deutschland
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17
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Rassam F, Roos E, van Lienden KP, van Hooft JE, Klümpen HJ, van Tienhoven G, Bennink RJ, Engelbrecht MR, Schoorlemmer A, Beuers UHW, Verheij J, Besselink MG, Busch OR, van Gulik TM. Modern work-up and extended resection in perihilar cholangiocarcinoma: the AMC experience. Langenbecks Arch Surg 2018; 403:289-307. [PMID: 29350267 PMCID: PMC5986829 DOI: 10.1007/s00423-018-1649-2] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 09/15/2017] [Indexed: 12/12/2022]
Abstract
AIM Perihilar cholangiocarcinoma (PHC) is a challenging disease and requires aggressive surgical treatment in order to achieve curation. The assessment and work-up of patients with presumed PHC is multidisciplinary, complex and requires extensive experience. The aim of this paper is to review current aspects of diagnosis, preoperative work-up and extended resection in patients with PHC from the perspective of our own institutional experience with this complex tumor. METHODS We provided a review of applied modalities in the diagnosis and work-up of PHC according to current literature. All patients with presumed PHC in our center between 2000 and 2016 were identified and described. The types of resection, surgical techniques and outcomes were analyzed. RESULTS AND CONCLUSION Upcoming diagnostic modalities such as Spyglass and combinations of serum biomarkers and molecular markers have potential to decrease the rate of misdiagnosis of benign, inflammatory disease. Assessment of liver function with hepatobiliary scintigraphy provides better information on the future remnant liver (FRL) than volume alone. The selective use of staging laparoscopy is advisable to avoid futile laparotomies. In patients requiring extended resection, selective preoperative biliary drainage is mandatory in cholangitis and when FRL is small (< 50%). Preoperative portal vein embolization (PVE) is used when FRL volume is less than 40% and optionally includes the left portal vein branches to segment 4. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) as alternative to PVE is not recommended in PHC. N2 positive lymph nodes preclude long-term survival. The benefit of unconditional en bloc resection of the portal vein bifurcation is uncertain. Along these lines, an aggressive surgical approach encompassing extended liver resection including segment 1, regional lymphadenectomy and conditional portal venous resection translates into favorable long-term survival.
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Affiliation(s)
- F Rassam
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands.
| | - E Roos
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - K P van Lienden
- Department of Radiology and Nuclear Medicine, Academic Medical Center, Amsterdam, The Netherlands
| | - J E van Hooft
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - H J Klümpen
- Department of Medical Oncology, Academic Medical Center, Amsterdam, The Netherlands
| | - G van Tienhoven
- Department of Radiotherapy, Academic Medical Center, Amsterdam, The Netherlands
| | - R J Bennink
- Department of Radiology and Nuclear Medicine, Academic Medical Center, Amsterdam, The Netherlands
| | - M R Engelbrecht
- Department of Radiology and Nuclear Medicine, Academic Medical Center, Amsterdam, The Netherlands
| | - A Schoorlemmer
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - U H W Beuers
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - J Verheij
- Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
| | - M G Besselink
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - O R Busch
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - T M van Gulik
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
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18
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Goldaracena N, Gorgen A, Sapisochin G. Current status of liver transplantation for cholangiocarcinoma. Liver Transpl 2018; 24:294-303. [PMID: 29024405 DOI: 10.1002/lt.24955] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 09/06/2017] [Accepted: 10/01/2017] [Indexed: 12/12/2022]
Abstract
Cholangiocarcinoma (CCA) is the second most common liver cancer, and it is associated with a poor prognosis. CCA can be divided into intrahepatic, hilar, and distal. Despite the subtype, the median survival is 12-24 months without treatment. Liver transplantation (LT) is recognized worldwide as a curative option for hepatocellular carcinoma. On the other hand, the initial results for LT for CCA were very poor mainly due to a lack of adequate patient selection. In the last 2 decades, improvements have been made in the management of unresectable hilar CCA, and the results of LT after neoadjuvant chemoradiation have been shown to be promising. This has prompted a consideration of hilar CCA as an indication for LT in some centers. Furthermore, some recent research has shown promising results after LT for patients with early stages of intrahepatic CCA. A better understanding of the best tools to prognosticate the outcomes of LT for CCA is still needed. Here, we aimed to review the role of LT for the treatment of patients with perihilar and intrahepatic CCA. Also, we will discuss the most recent advances in the field and the future direction of the management of this disease in an era of transplantation oncology. Liver Transplantation 24 294-303 2018 AASLD.
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Affiliation(s)
- Nicolás Goldaracena
- Multi-Organ Transplant, Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Andre Gorgen
- Multi-Organ Transplant, Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Gonzalo Sapisochin
- Multi-Organ Transplant, Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada
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Validation of the Mayo Clinic Staging System in Determining Prognoses of Patients With Perihilar Cholangiocarcinoma. Clin Gastroenterol Hepatol 2017; 15:1930-1939.e3. [PMID: 28532698 DOI: 10.1016/j.cgh.2017.04.044] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 03/22/2017] [Accepted: 04/21/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Most systems for staging perihilar cholangiocarcinoma (PHC) have been developed for the minority of patients with resectable disease. The recently developed Mayo Clinic system for staging PHC requires only clinical and radiologic variables, but has not yet been validated. We performed a retrospective study to validate the Mayo Clinic staging system. METHODS We identified consecutive patients with suspected PHC who were evaluated and treated at 2 tertiary centers in The Netherlands, from January 2002 through December 2014. Baseline characteristics (performance status, carbohydrate antigen 19-9 level) used in the staging system were collected from medical records and imaging parameters (tumor size, suspected vascular involvement, and metastatic disease) were reassessed by 2 experienced abdominal radiologists. Overall survival was analyzed using the Kaplan-Meier method and comparison of staging groups was performed using the log-rank test and Cox proportional hazard regression analysis. Discriminative performance was quantified by the concordance index and compared with the radiologic TNM staging of the American Joint Committee on Cancer (7th ed). RESULTS PHCs from 600 patients were staged according to the Mayo Clinic model (23 stage I, 80 stage II, 357 stage III, and 140 stage IV). The median overall survival time was 11.6 months. The median overall survival times for patients with stages I, II, III, and IV were 33.2 months, 19.7 months, 12.1 months, and 6.0 months, respectively; with hazard ratios of 1.0 (reference), 2.02 (95% confidence interval [CI], 1.14-3.58), 2.71 (95% CI, 1.59-4.64), and 4.00 (95% CI, 2.30-6.95), respectively (P < .001). The concordance index score was 0.59 for the entire cohort (95% CI, 0.56-0.61). The Mayo Clinic model performed slightly better than the radiologic American Joint Committee on Cancer TNM system. CONCLUSIONS In a retrospective study of 600 patients with PHC, we validated the Mayo Clinic system for staging PHC. This 4-tier staging system may aid clinicians in making treatment decisions, such as referral for surgery, and predicting survival times.
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Blechacz B. Cholangiocarcinoma: Current Knowledge and New Developments. Gut Liver 2017; 11:13-26. [PMID: 27928095 PMCID: PMC5221857 DOI: 10.5009/gnl15568] [Citation(s) in RCA: 343] [Impact Index Per Article: 42.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 12/17/2015] [Indexed: 12/14/2022] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common primary malignancy. Although it is more common in Asia, its incidence in Europe and North America has significantly increased in recent decades. The prognosis of CCA is dismal. Surgery is the only potentially curative treatment, but the majority of patients present with advanced stage disease, and recurrence after resection is common. Over the last two decades, our understanding of the molecular biology of this malignancy has increased tremendously, diagnostic techniques have evolved, and novel therapeutic approaches have been established. This review discusses the changing epidemiologic trends and provides an overview of newly identified etiologic risk factors for CCA. Furthermore, the molecular pathogenesis is discussed as well as the influence of etiology and biliary location on the mutational landscape of CCA. This review provides an overview of the diagnostic evaluation of CCA and its staging systems. Finally, new therapeutic options are critically reviewed, and future therapeutic strategies discussed.
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Affiliation(s)
- Boris Blechacz
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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21
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Cadamuro M, Stecca T, Brivio S, Mariotti V, Fiorotto R, Spirli C, Strazzabosco M, Fabris L. The deleterious interplay between tumor epithelia and stroma in cholangiocarcinoma. Biochim Biophys Acta Mol Basis Dis 2017; 1864:1435-1443. [PMID: 28757170 DOI: 10.1016/j.bbadis.2017.07.028] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Revised: 07/26/2017] [Accepted: 07/26/2017] [Indexed: 12/15/2022]
Abstract
Prognosis of cholangiocarcinoma, a devastating liver epithelial malignancy characterized by early invasiveness, remains very dismal, though its incidence has been steadily increasing. Evidence is mounting that in cholangiocarcinoma, tumor epithelial cells establish an intricate web of mutual interactions with multiple stromal components, largely determining the pervasive behavior of the tumor. The main cellular components of the tumor microenvironment (i.e. myofibroblasts, macrophages, lymphatic endothelial cells), which has been recently termed as 'tumor reactive stroma', are recruited and activated by neoplastic cells, and in turn, deleteriously mold tumor behavior by releasing a huge variety of paracrine signals, including cyto/chemokines, growth factors, morphogens and proteinases. An abnormally remodeled and stiff extracellular matrix favors and supports these cell interactions. Although the mechanisms responsible for the generation of tumor reactive stroma are largely uncertain, hypoxia presumably plays a central role. In this review, we will dissect the intimate relationship among the different cell elements cooperating within this complex 'ecosystem', with the ultimate goal to pave the way for a deeper understanding of the mechanisms underlying cholangiocarcinoma aggressiveness, and possibly, to foster the development of innovative, combinatorial therapies aimed at halting tumor progression. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
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Affiliation(s)
- Massimiliano Cadamuro
- Department of Medicine and Surgery, University of Milan-Bicocca School of Medicine, 20126 Milan, Italy; International Center for Digestive Health (ICDH), University of Milan-Bicocca School of Medicine, 20126 Milan, Italy
| | - Tommaso Stecca
- Department of Surgical, Oncological, and Gastroenterological Sciences (DiSCOG), University of Padova, 35128 Padova, Italy
| | - Simone Brivio
- Department of Medicine and Surgery, University of Milan-Bicocca School of Medicine, 20126 Milan, Italy
| | - Valeria Mariotti
- Department of Molecular Medicine, University of Padua School of Medicine, 35121 Padua, Italy
| | - Romina Fiorotto
- International Center for Digestive Health (ICDH), University of Milan-Bicocca School of Medicine, 20126 Milan, Italy; Liver Center, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Carlo Spirli
- International Center for Digestive Health (ICDH), University of Milan-Bicocca School of Medicine, 20126 Milan, Italy; Liver Center, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Mario Strazzabosco
- Department of Medicine and Surgery, University of Milan-Bicocca School of Medicine, 20126 Milan, Italy; International Center for Digestive Health (ICDH), University of Milan-Bicocca School of Medicine, 20126 Milan, Italy; Liver Center, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Luca Fabris
- International Center for Digestive Health (ICDH), University of Milan-Bicocca School of Medicine, 20126 Milan, Italy; Department of Molecular Medicine, University of Padua School of Medicine, 35121 Padua, Italy; Liver Center, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA.
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Visseren T, Darwish Murad S. Recurrence of primary sclerosing cholangitis, primary biliary cholangitis and auto-immune hepatitis after liver transplantation. Best Pract Res Clin Gastroenterol 2017. [PMID: 28624107 DOI: 10.1016/j.bpg.2017.04.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Liver transplantation is a well-accepted treatment for decompensated chronic liver disease due to primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and auto-immune hepatitis (AIH). Survival after liver transplantation is generally good with 1 and 5-year survival rates around 90% and 70-85%. After transplantation, however, these diseases recur in 8.6-27% (rPSC), 10.9-42.3% (rPBC) and 7-42% (rAIH), and this poses significant challenges in terms of management and graft outcome in these patients. In this review we discuss the incidence, clinical presentation, challenges in diagnosis, reported risk factors and impact on post-transplant outcomes of recurrence of PSC, PBC and AIH after liver transplantation. We also discuss some of the limitations of current investigations and formulate idea's for future research objectives.
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Affiliation(s)
- T Visseren
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Surgery, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
| | - S Darwish Murad
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
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Saffioti F, Gurusamy KS, Hawkins N, Toon CD, Tsochatzis E, Davidson BR, Thorburn D, Cochrane Hepato‐Biliary Group. Pharmacological interventions for primary sclerosing cholangitis: an attempted network meta-analysis. Cochrane Database Syst Rev 2017; 3:CD011343. [PMID: 28417463 PMCID: PMC6464655 DOI: 10.1002/14651858.cd011343.pub2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Primary sclerosing cholangitis is a chronic cholestatic liver disease that is associated with both hepatobiliary and colorectal malignancies, which can result in liver cirrhosis and its complications. The optimal pharmacological treatment for patients with primary sclerosing cholangitis remains controversial. OBJECTIVES To assess the comparative benefits and harms of different pharmacological interventions in people with primary sclerosing cholangitis by performing a network meta-analysis, and to generate rankings of available pharmacological interventions according to their safety and efficacy. Given that it was not possible to assess whether potential effect modifiers were similar across comparisons, we did not perform the network meta-analysis but instead used standard Cochrane methods.When trials begin to provide an adequate description of potential effect modifiers, we will attempt to conduct network meta-analysis. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Science Citation Index - Expanded, the WHO International Clinical Trials Registry Platform, and randomised controlled trials registers until February 2017 to identify randomised clinical trials (RCT) on pharmacological interventions for primary sclerosing cholangitis. SELECTION CRITERIA We included only RCTs, irrespective of language, blinding, or publication status, in which participants were given a diagnosis of primary sclerosing cholangitis. We excluded trials that included previously liver-transplanted participants. We considered any of various pharmacological interventions compared with one other or with placebo. We excluded trials that compared different doses of various pharmacological interventions or that reported different treatment durations, except for ursodeoxycholic acid (UDCA). As UDCA is the drug most commonly investigated for primary sclerosing cholangitis, we performed a second analysis in which we stratified the dose of UDCA. DATA COLLECTION AND ANALYSIS We calculated the odds ratio and the rate ratio with 95% confidence intervals (CIs) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS We identified 22 RCTs in which 1211 participants were randomised to 13 different interventions. Most were placebo-controlled trials. Trials had few restrictions apart from an established diagnosis of primary sclerosing cholangitis, evidence of cholestasis, absence of decompensated liver disease, and absence of malignancy. However, some trials included symptomatic participants only, and others included both symptomatic and asymptomatic participants. A total of 11 RCTs (706 participants) provided data for one or more outcomes. The period of follow-up ranged from three months to three years in most trials. Only three trials reported follow-up longer than three years. Investigators found no evidence of differences in important clinical benefits such as reduction in mortality at maximal follow-up and improvement in health-related quality of life. Primary outcomes Mortality: Effect estimates: colchicine versus placebo: odds ratio 0.44, 95% CI 0.04 to 5.07, participants = 84, one trial; penicillamine versus placebo: odds ratio 1.18, 95% CI 0.39 to 3.58, participants = 70, one trial; steroids versus placebo: odds ratio 3.00, 95% CI 0.10 to 90.96, participants = 11, one trial; ursodeoxycholic acid versus placebo: odds ratio 1.51, 95% CI 0.63 to 3.63, participants = 348, two trials, I2 = 0%; vancomycin versus placebo: not estimable because no events in either group, participants = 29, one trial. Serious adverse events (proportion): Effect estimates: infliximab versus placebo: odds ratio not estimable (because of zero events in both arms), participants = 7, one trial; steroids versus placebo: odds ratio 20.00, 95% CI 0.93 to 429.90, participants = 11, one trial; vancomycin versus placebo: not estimable because no events in either group, participants = 29, one trial. Serious adverse events (number): Effect estimates: infliximab versus placebo: rate ratio 0.80, 95% CI 0.02 to 40.44, participants = 7, one trial; penicillamine versus placebo: rate ratio 13.60, 95% CI 0.78 to 237.83, participants = 70, one trial; steroids versus placebo: rate ratio 3.32, 95% CI 0.71 to 15.62, participants = 11, one trial. Adverse events (proportion): Effect estimates: steroids versus placebo: odds ratio 20.00, 95% CI 0.93 to 429.90, participants = 11, one trial; ursodeoxycholic acid versus placebo: odds ratio 1.22, 95% CI 0.68 to 2.17, participants = 198, one trial; vancomycin versus placebo: not estimable because no events in either group, participants = 29, one trial. Adverse events (number): Effect estimates: cyclosporin versus placebo: rate ratio 2.64, 95% CI 0.99 to 7.03, participants = 26, one trial; steroids versus placebo: rate ratio 3.32, 95% CI 0.71 to 15.62, participants = 11, one trial; ursodeoxycholic acid plus metronidazole versus ursodeoxycholic acid: rate ratio 2.36, 95% CI 0.98 to 5.71, participants = 71, one trial. Health-related quality of life: ursodeoxycholic acid versus placebo: mean difference 1.30, 95% CI -5.61 to 8.21, participants = 198, one trial (Short Form (SF)-36 General Health Scale). Secondary outcomes Studies provided no evidence of differences in clinical benefits such as a reduction in the requirement for liver transplantation or a reduction in the incidence proportion of cholangiocarcinoma. One small trial (29 participants) comparing vancomycin versus placebo reported no malignancies, no liver decompensation, and no liver transplantation in either group after a very short follow-up period of 12 weeks after treatment. None of the remaining trials clearly reported other clinical benefits such as decreased development of all malignancies, colorectal cancer, liver decompensation, time to liver decompensation, time to liver transplantation, or requirement for cholecystectomy to allow comparisons between different interventions. SOURCE OF FUNDING Fifteen trials reported the source of funding; three were funded by parties without vested interest in results of the trial, and 12 were funded in part or in full by drug companies. AUTHORS' CONCLUSIONS Evidence is currently insufficient to show differences in effectiveness measures such as mortality, health-related quality of life, cirrhosis, or liver transplantation between any active pharmacological intervention and no intervention. However, trials were at high risk of bias and included small numbers of participants, had short follow-up periods, and reported few clinical outcomes. An urgent need exists to identify an effective medical treatment for primary sclerosing cholangitis through well-designed RCTs with adequate follow-up that aim to identify differences in outcomes important to people with primary sclerosing cholangitis.
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Affiliation(s)
- Francesca Saffioti
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
- University of MessinaDepartment of Clinical and Experimental Medicine, Division of Clinical and Molecular HepatologyVia Consolare Valeria, 1MessinaMessinaItaly98125
| | - Kurinchi Selvan Gurusamy
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryRoyal Free HospitalRowland Hill StreetLondonUKNW3 2PF
| | - Neil Hawkins
- London School of Hygiene and Tropical MedicineHSRPKeppel StreetLondonUKWC1E 7HT
| | - Clare D Toon
- West Sussex County CouncilPublic Health & Social Research UnitThe Grange, County Hall CampusTower StreetChichesterWest SussexUKPO19 1QT
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
| | - Brian R Davidson
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryRoyal Free HospitalRowland Hill StreetLondonUKNW3 2PF
| | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentrePond StreetHampsteadLondonUKNW3 2QG
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Montano-Loza AJ, Bhanji RA, Wasilenko S, Mason AL. Systematic review: recurrent autoimmune liver diseases after liver transplantation. Aliment Pharmacol Ther 2017; 45:485-500. [PMID: 27957759 DOI: 10.1111/apt.13894] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 10/21/2016] [Accepted: 11/17/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Autoimmune liver diseases (AILD) constitute the third most common indication for liver transplantation (LT) worldwide. Outcomes post LT are generally good but recurrent disease is frequently observed. AIMS To describe the frequency and risk factors associated with recurrent AILD post-LT and provide recommendations to reduce the incidence of recurrence based on levels of evidence. METHODS A systematic review was performed for full-text papers published in English-language journals, using the keywords 'autoimmune hepatitis (AIH)', 'primary biliary cholangitis and/or cirrhosis (PBC)', 'primary sclerosing cholangitis (PSC)', 'liver transplantation' and 'recurrent disease'. Management strategies to reduce recurrence after LT were classified according to grade and level of evidence. RESULTS Survival rates post-LT are approximately 90% and 70% at 1 and 5 years and recurrent disease occurs in a range of 10-50% of patients with AILD. Recurrent AIH is associated with elevated liver enzymes and IgG before LT, lymphoplasmacytic infiltrates in the explants and lack of steroids after LT (Grade B). Tacrolimus use is associated with increased risk; use of ciclosporin and preventive ursodeoxycholic acid with reduced risk of PBC recurrence (all Grade B). Intact colon, active ulcerative colitis and early cholestasis are associated with recurrent PSC (Grade B). CONCLUSIONS Recommendations based on grade A level of evidence are lacking. The need for further study and management includes active immunosuppression before liver transplantation and steroid use after liver transplantation in autoimmune hepatitis; selective immunosuppression with ciclosporin and preventive ursodeoxycholic acid treatment for primary biliary cholangitis; and improved control of inflammatory bowel disease or even colectomy in primary sclerosing cholangitis.
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Affiliation(s)
- A J Montano-Loza
- Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
| | - R A Bhanji
- Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
| | - S Wasilenko
- Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
| | - A L Mason
- Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
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Kyrochristos ID, Glantzounis GK, Ziogas DE, Gizas I, Schizas D, Lykoudis EG, Felekouras E, Machairas A, Katsios C, Liakakos T, Cho WC, Roukos DH. From Clinical Standards to Translating Next-Generation Sequencing Research into Patient Care Improvement for Hepatobiliary and Pancreatic Cancers. Int J Mol Sci 2017; 18:180. [PMID: 28106782 PMCID: PMC5297812 DOI: 10.3390/ijms18010180] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Revised: 12/19/2016] [Accepted: 12/27/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatobiliary and pancreatic (HBP) cancers are associated with high cancer-related death rates. Surgery aiming for complete tumor resection (R0) remains the cornerstone of the treatment for HBP cancers. The current progress in the adjuvant treatment is quite slow, with gemcitabine chemotherapy available only for pancreatic ductal adenocarcinoma (PDA). In the advanced and metastatic setting, only two targeted drugs have been approved by the Food & Drug Administration (FDA), which are sorafenib for hepatocellular carcinoma and erlotinib for PDA. It is a pity that multiple Phase III randomized control trials testing the efficacy of targeted agents have negative results. Failure in the development of effective drugs probably reflects the poor understanding of genome-wide alterations and molecular mechanisms orchestrating therapeutic resistance and recurrence. In the post-ENCODE (Encyclopedia of DNA Elements) era, cancer is referred to as a highly heterogeneous and systemic disease of the genome. The unprecedented potential of next-generation sequencing (NGS) technologies to accurately identify genetic and genomic variations has attracted major research and clinical interest. The applications of NGS include targeted NGS with potential clinical implications, while whole-exome and whole-genome sequencing focus on the discovery of both novel cancer driver genes and therapeutic targets. These advances dictate new designs for clinical trials to validate biomarkers and drugs. This review discusses the findings of available NGS studies on HBP cancers and the limitations of genome sequencing analysis to translate genome-based biomarkers and drugs into patient care in the clinic.
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Affiliation(s)
- Ioannis D Kyrochristos
- Centre for Biosystems and Genome Network Medicine, Ioannina University, 45110 Ioannina, Greece.
- Department of Surgery, Ioannina University Hospital, 45110 Ioannina, Greece.
| | | | - Demosthenes E Ziogas
- Centre for Biosystems and Genome Network Medicine, Ioannina University, 45110 Ioannina, Greece.
- Department of Surgery, 'G. Hatzikosta' General Hospital, 45001 Ioannina, Greece.
| | | | - Dimitrios Schizas
- 1st Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece.
| | - Efstathios G Lykoudis
- Department of Plastic Surgery, Ioannina University School of Medicine, 45110 Ioannina, Greece.
| | - Evangelos Felekouras
- 1st Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece.
| | - Anastasios Machairas
- Third Department of Surgery, Attikon General Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece.
| | - Christos Katsios
- Department of Surgery, Ioannina University Hospital, 45110 Ioannina, Greece.
| | - Theodoros Liakakos
- 1st Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece.
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong, China.
| | - Dimitrios H Roukos
- Centre for Biosystems and Genome Network Medicine, Ioannina University, 45110 Ioannina, Greece.
- Department of Surgery, Ioannina University Hospital, 45110 Ioannina, Greece.
- Biomedical Research Foundation of the Academy of Athens (BRFAA), 11527 Athens, Greece.
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Abstract
UNLABELLED Introduction and aims. Cholangiocarcinomas are a heterogeneous group of tumors that can be classified into three clinically distinct types of cancers, intrahepatic, perihilar and distal cholangiocarcinoma. The inconsistent use of nomenclature for these cancers has obscured a true knowledge of the epidemiology, natural history and response to therapy of these cancers. Our aims were to define demographic characteristics, management and outcomes of these three distinct cancer types. MATERIALS AND METHODS A retrospective study of patients enrolled in an institutional cancer registry from 1992 to 2010. Median survival was compared between different treatment modalities over three time periods for the three types of cholangiocarcinoma at different stages of the disease using Kaplan Meyer analysis. RESULTS 242 patients were identified. All cases were reviewed and classified into intrahepatic (90 patients), distal (48 patients) or perihilar (104 patients) cholangiocarcinomas. These cancers differed in median age of onset, gender distribution, median survival and stage. 13.8% of patients presented with stage I, 5.8% with stage II, 9.6% with stage III, 28% with stage IV, with 41.8% having unknown stage. The overall median survival was 15.8 months, and was 23, 25, 14, and 4.5 months for stages I, II, III, and IV respectively. Surgery improved survival in both early and advanced stages. Multimodality therapies further improved outcomes, particularly for perihilar cholangiocarcinoma. CONCLUSION Perihilar, distal and intrahepatic cholangiocarcinoma vary in their presentation, natural history and therapeutic approach to management. A consistently applied classification is essential for meaningful interpretation of studies of these cancers.
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Affiliation(s)
- David Waseem
- Department of Transplantation, Mayo Clinic Florida, USA
| | - Patel Tushar
- Department of Transplantation, Mayo Clinic Florida, USA
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Y-Shaped, Self-Expanding Metallic Stents (SEMS) to Drain Malignant Strictures of the Liver Hilum: Y Are They Better? Dig Dis Sci 2017; 62:10-12. [PMID: 27853899 DOI: 10.1007/s10620-016-4350-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Prognostic Significance of the Histologic Response of Perihilar Cholangiocarcinoma to Preoperative Neoadjuvant Chemoradiation in Liver Explants. Am J Surg Pathol 2016; 40:510-8. [PMID: 26752544 DOI: 10.1097/pas.0000000000000588] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Perihilar cholangiocarcinoma (pCCA) has a dismal prognosis. Protocols incorporating chemotherapy, radiotherapy, and liver transplantation (LT) have emerged as curative options for unresectable tumors with 70% 5-year survival rates. We aimed to assess the value of extent of residual tumor (ERT) and other pathologic factors following chemoradiation in predicting outcome; 152 liver explants with pCCA treated with neoadjuvant chemoradiation and LT between 1993 and 2013 were reviewed for ERT, pathologic stage, histologic grade, and perineural and lymphovascular invasion. ERT was quantified as the percentage of viable carcinoma in the tumor bed. Tumors were classified into 4 ERT categories: (1) complete/near-complete response (≤1% ERT); (2) marked response (>1 to <10% ERT); (3) moderate response (10 to <30% ERT); and (4) minimal response (≥30% ERT). Overall 5-year survival rate was 69%. 5-year disease-free estimate was 74%. 57%, 16%, 18%, and 9% of explants were placed in ERT categories 1, 2, 3, and 4, respectively. ERT correlated significantly with the overall 5-year survival rate and 5-year, disease-free estimate by univariate (P<0.0001) and multivariate analysis (P=0.004 and 0.009, respectively). By multivariate analysis, pathologic stage was also an independent predictor of recurrence (P=0.003). Other variables that correlated with risk of death and recurrence by univariate analysis included perineural (P<0.0001) and lymphovascular invasion (P<0.0001), absence of primary sclerosing cholangitis (P=0.006 and P<0.0001, respectively), and pretreatment CA19-9 level (P=0.001 and 0.02, respectively). Histologic grade did not predict outcome. In summary, ERT independently predicts outcome in pCCA patients following neoadjuvant chemoradiation and LT and can stratify patient prognosis.
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Updated Management of Malignant Biliary Tract Tumors: An Illustrative Review. J Vasc Interv Radiol 2016; 27:1056-69. [DOI: 10.1016/j.jvir.2016.01.149] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Revised: 12/12/2015] [Accepted: 01/27/2016] [Indexed: 12/18/2022] Open
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Mantel HTJ, Westerkamp AC, Adam R, Bennet WF, Seehofer D, Settmacher U, Sánchez-Bueno F, Fabregat Prous J, Boleslawski E, Friman S, Porte RJ, European Liver and Intestine Transplant Association (ELITA). Strict Selection Alone of Patients Undergoing Liver Transplantation for Hilar Cholangiocarcinoma Is Associated with Improved Survival. PLoS One 2016; 11:e0156127. [PMID: 27276221 PMCID: PMC4898828 DOI: 10.1371/journal.pone.0156127] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Accepted: 05/10/2016] [Indexed: 12/17/2022] Open
Abstract
Liver transplantation for hilar cholangiocarcinoma (hCCA) has regained attention since the Mayo Clinic reported their favorable results with the use of a neo-adjuvant chemoradiation protocol. However, debate remains whether the success of the protocol should be attributed to the neo-adjuvant therapy or to the strict selection criteria that are being applied. The aim of this study was to investigate the value of patient selection alone on the outcome of liver transplantation for hCCA. In this retrospective study, patients that were transplanted for hCCA between1990 and 2010 in Europe were identified using the European Liver Transplant Registry (ELTR). Twenty-one centers reported 173 patients (69%) of a total of 249 patients in the ELTR. Twenty-six patients were wrongly coded, resulting in a study group of 147 patients. We identified 28 patients (19%) who met the strict selection criteria of the Mayo Clinic protocol, but had not undergone neo-adjuvant chemoradiation therapy. Five–year survival in this subgroup was 59%, which is comparable to patients with pretreatment pathological confirmed hCCA that were transplanted after completion of the chemoradiation protocol at the Mayo Clinic. In conclusion, although the results should be cautiously interpreted, this study suggests that with strict selection alone, improved survival after transplantation can be achieved, approaching the Mayo Clinic experience.
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Affiliation(s)
- Hendrik T. J. Mantel
- Department of Hepato-Pancreatico-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Andrie C. Westerkamp
- Department of Hepato-Pancreatico-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - René Adam
- Department of Hepatobiliary Surgery, Hôpital Paul Brousse, University of Paris-Sud, Villejuif, France
| | - William F. Bennet
- Transplant Institute, Sahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Daniel Seehofer
- Department of General, Visceral and Transplantation Surgery, Charité Campus Virchow, Berlin, Germany
| | - Utz Settmacher
- Department of General, Visceral and Vascular Surgery, University of Jena, Jena, Germany
| | - Francisco Sánchez-Bueno
- Department of Surgery and Liver and Pancreas Transplantation, Virgen de la Arrixaca Clinic and University Hospital, Murcia, Spain
| | - Joan Fabregat Prous
- Department of Hepato-Pancreatico- Biliary Surgery and Liver Transplantation, University Hospital de Bellvitge, University of Barcelona, Barcelona, Spain
| | - Emmanuel Boleslawski
- Department of Digestive Surgery and Transplantation, Lille University Medical Center, University of Lille Nord de France, Lille, France
| | - Styrbjörn Friman
- Transplant Institute, Sahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Robert J. Porte
- Department of Hepato-Pancreatico-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- * E-mail:
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Fluorescence in situ hybridization compared with conventional cytology for the diagnosis of malignant biliary tract strictures in Asian patients. Gastrointest Endosc 2016; 83:1228-35. [PMID: 26684604 DOI: 10.1016/j.gie.2015.11.037] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 11/25/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Fluorescence in situ hybridization (FISH) has improved the diagnostic performance of cytology for the evaluation of malignant biliary strictures in the United States and Europe. The utility of FISH for the diagnosis of biliary strictures in Asia is currently unknown. We aimed to compare the sensitivity of FISH and conventional cytology for the diagnosis of malignant biliary strictures in Thai patients. METHODS A prospective study was performed at 2 university hospitals between 2010 and 2013. Patients being evaluated for malignant-appearing biliary strictures were included (N = 99). Bile duct brushings were collected and assessed by cytology and FISH. Sensitivities with 95% confidence intervals of cytology and FISH were the main outcome measures. RESULTS The overall sensitivities of cytology and FISH were 38% and 55%, respectively (P = .001). For those with a diagnosis of cancer based on clinical evidence without biopsy confirmation (n = 44), the sensitivities of cytology and FISH were 43% and 57%, respectively (P = .06). For the 49 patients for whom a cancer diagnosis was confirmed by pathology, FISH had a significantly higher sensitivity than cytology, with a sensitivity of 53% versus 33%, respectively (P = .008). CONCLUSIONS FISH improves the diagnostic performance of cytology and can be used as a complementary tool to bile duct brushing and biopsy for the evaluation of malignancy in biliary strictures in Asian populations.
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Heits N, Heinze T, Bernsmeier A, Kerber J, Hauser C, Becker T, Kalthoff H, Egberts JH, Braun F. Influence of mTOR-inhibitors and mycophenolic acid on human cholangiocellular carcinoma and cancer associated fibroblasts. BMC Cancer 2016; 16:322. [PMID: 27206490 PMCID: PMC4875636 DOI: 10.1186/s12885-016-2360-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 05/12/2016] [Indexed: 12/19/2022] Open
Abstract
Background The incidence of Cholangiocellular Carcinoma (CCA) is increasing in the western world. The tumour has a high proportion of desmoplastic stroma and is correlated with a worse prognosis when cancer associated myofibroblasts (CAFs) are present. Recent studies showed promising results after liver transplantation (LTx) in non-resectable early stage CCA. Mycophenolic acid (MPA) and the mTor inhibitor Everolimus are used to prevent organ rejection but recently were shown to exhibit an antiproliferative effect on CCA-cells. Little is known about the influence of immunosuppressive drugs on tumour cell proliferation and migration after paracrine stimulation by CAFs. Moreover, it is still unknown, which signaling pathways are activated following these specific cell-cell interactions. Methods CCA cell lines HuCCT1 and TFK1 were utilized for the study. CAFs were derived from resected CCA cancer tissue. Cell viability was measured by the crystal violet assay and tumour cell invasion was quantified using a modified co-culture transmigration assay. Semiquantitative cytokine-expression was measured using a cytokine-array. Protein expression and phosphorylation of ERK, STAT3 and AKT was determined by Western-blot analysis. Results CCA cells treated with MPA exhibited a dose related decrease in cell viability in contrast to Cyclosporine A (CSA) treatment which had no effect on cell viability. Everolimus significantly inhibited proliferation at very low concentrations. The pro-invasive effect of CAFs in co-culture transmigration assay was significantly reduced by Everolimus at a concentration of 1nM (p = 0.047). In contrast, MPA and CSA showed no effect on tumour cell invasion. Treatment of CAFs with 1nM Everolimus showed a significant reduction in the expression of IL 8, IL 13, MCP1, MIF and Serpin E1. CCA-cells showed significant increases in phosphorylation of ERK, STAT3 and AKT under the influence of conditioned CAF-media. This effect was suppressed by Everolimus. Conclusions The secretion of proinflammatory cytokines by CAFs may lead to increased activation of JAK/STAT3-, ERK- and AKT-signaling and increased migration of CCA-cells. Everolimus abrogates this effect and inhibits proliferation of CCA-cells even at low concentrations. LTx for non-resectable early stage CCA is currently performed in several clinical studies. Consistent with a role for common immunosuppressants in inhibiting tumour cell-proliferation and -invasion, our study indicates that a combination of standard therapies with Everolimus and MPA is a promising therapy option to treat CCA following LTx.
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Affiliation(s)
- Nils Heits
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Strasse 3 (Haus 18), 24105, Kiel, Germany.
| | - Tillmann Heinze
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Strasse 3 (Haus 18), 24105, Kiel, Germany.,Division of Molecular Oncology, Institute for Experimental Cancer Research, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller Str. 3, 24105, Kiel, Germany
| | - Alexander Bernsmeier
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Strasse 3 (Haus 18), 24105, Kiel, Germany
| | - Jannik Kerber
- Division of Molecular Oncology, Institute for Experimental Cancer Research, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller Str. 3, 24105, Kiel, Germany
| | - Charlotte Hauser
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Strasse 3 (Haus 18), 24105, Kiel, Germany
| | - Thomas Becker
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Strasse 3 (Haus 18), 24105, Kiel, Germany
| | - Holger Kalthoff
- Division of Molecular Oncology, Institute for Experimental Cancer Research, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller Str. 3, 24105, Kiel, Germany
| | - Jan-Hendrik Egberts
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Strasse 3 (Haus 18), 24105, Kiel, Germany
| | - Felix Braun
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, Arnold-Heller-Strasse 3 (Haus 18), 24105, Kiel, Germany
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Marret G, Neuzillet C, Rousseau B, Tournigand C. [Medical management of cholangiocarcinomas in 2015]. Bull Cancer 2016; 103:389-99. [PMID: 26922666 DOI: 10.1016/j.bulcan.2016.01.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2015] [Revised: 01/11/2016] [Accepted: 01/19/2016] [Indexed: 12/21/2022]
Abstract
Cholangiocarcinoma is a rare malignancy carrying a poor prognosis. Most patients are diagnosed with advanced-stage disease and are then ineligible for surgical resection, which is the only potentially curative therapeutic modality. The aim of this article is to provide an up-to-date review of medical management of patients with cholangiocarcinoma. The benefit of adjuvant therapy in patients undergoing curative-intent surgery is under evaluation. Combination chemotherapy with gemcitabine and platinum is the standard first-line treatment for patients with advanced cholangiocarcinoma. Targeted agents are not currently recommended due to limited data on use in this setting. The role of second-line chemotherapy is not established in advanced cholangiocarcinoma. Identification of predictive and prognostic markers to select patients who could benefit from second-line therapy is a major issue. A better understanding of the biological and molecular mechanisms underlying the carcinogenesis and the phenotypic heterogeneity of cholangiocarcinoma may path the way of new therapeutic strategies.
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Affiliation(s)
- Grégoire Marret
- Assistance publique-Hôpitaux de Paris (AP-HP), université Paris Est Créteil (UPEC), hôpital Henri-Mondor, service d'oncologie médicale, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94000 Créteil, France
| | - Cindy Neuzillet
- Assistance publique-Hôpitaux de Paris (AP-HP), université Paris Est Créteil (UPEC), hôpital Henri-Mondor, service d'oncologie médicale, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94000 Créteil, France.
| | - Benoît Rousseau
- Assistance publique-Hôpitaux de Paris (AP-HP), université Paris Est Créteil (UPEC), hôpital Henri-Mondor, service d'oncologie médicale, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94000 Créteil, France
| | - Christophe Tournigand
- Assistance publique-Hôpitaux de Paris (AP-HP), université Paris Est Créteil (UPEC), hôpital Henri-Mondor, service d'oncologie médicale, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94000 Créteil, France
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Abstract
Liver transplantation (LT) is an established lifesaving therapy for patients with cholestatic liver diseases, including primary cholestatic diseases, namely primary sclerosing cholangitis and primary biliary cirrhosis, as well as secondary forms of cholestatic liver disease, including those with cholestatic complications of LT needing a retransplant. Patients with cholestatic liver diseases can be transplanted for complications of end-stage liver disease or for disease-specific symptoms before the onset of end-stage liver disease. These patients should be regularly assessed. Patient survival after LT for cholestatic liver diseases is generally better than for other indications.
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Affiliation(s)
- Vandana Khungar
- Division of Gastroenterology, University of Pennsylvania, 3400 Spruce Street, 2 Dulles, Philadelphia, PA 19104, USA
| | - David Seth Goldberg
- Division of Gastroenterology, University of Pennsylvania, Blockley Hall, 423 Guardian Drive, Room 730, Philadelphia, PA 19104, USA.
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Gulamhusein AF, Sanchez W. Liver transplantation in the management of perihilar cholangiocarcinoma. Hepat Oncol 2015; 2:409-421. [PMID: 30191020 DOI: 10.2217/hep.15.30] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common primary hepatic neoplasm and accounts for 10-20% of hepatobiliary cancer-related deaths. The prognosis of patients with CCA is poor with 5-year survival rates of 10%, partially due to the limited effective treatment options that exist for this disease. In this review, we discuss the evolving role of liver transplantation in the management of patients with perihilar CCA (pCCA). We specifically discuss the Mayo Clinic protocol of neoadjuvant chemoradiation followed by liver transplantation in selected patients with pCCA and describe pretransplant, peritransplant, and post-transplant considerations and challenges with this approach. Finally, we review local, national and international outcomes and discuss future directions in optimizing this treatment strategy for patients who otherwise have few therapeutic options and limited survival.
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Affiliation(s)
- Aliya F Gulamhusein
- Division of Gastroenterology & Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - William Sanchez
- Division of Gastroenterology & Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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EXP CLIN TRANSPLANTExp Clin Transplant 2015; 13. [DOI: 10.6002/ect.2015.0048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Role of surgery in cholangiocarcinoma: From resection to transplantation. Best Pract Res Clin Gastroenterol 2015; 29:295-308. [PMID: 25966429 DOI: 10.1016/j.bpg.2015.02.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Revised: 01/12/2015] [Accepted: 02/07/2015] [Indexed: 02/06/2023]
Abstract
The treatment of cholangiocarcinoma (CCA) represents a major challenge to modern medicine. Diagnostics and treatment modalities are complex and require close interdisciplinary work-up. However, surgical resection currently offers the only potentially curative treatment option. Improved peri-operative strategies as well as optimized surgical techniques have generated significantly increased survival chances for patients in recent years. Complete tumor resection is the key parameter to long-term survival. In spite of expanded surgical limits R0 resection cannot be achieved in some cases as parenchymal disease may limit the extent of resection. Although liver transplantation (LT) is not a standard therapy for CCA today, it may be an option in such selected cases. Protocols including neo-adjuvant radio-chemotherapy and staging-lymphadenectomy before LT have generated impressive results in the recent past. Since palliative options generate only short-term survival extension LT for CCA has lately been discussed more extensively after the procedure had been abandoned due to dismal survival data in the 1990-years. This review offers a comprehensive picture of the current surgical treatment option for cholangiocarcinoma.
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Wilson JM, Kunnimalaiyaan S, Kunnimalaiyaan M, Gamblin TC. Inhibition of the AKT pathway in cholangiocarcinoma by MK2206 reduces cellular viability via induction of apoptosis. Cancer Cell Int 2015; 15:13. [PMID: 25674039 PMCID: PMC4324843 DOI: 10.1186/s12935-015-0161-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2014] [Accepted: 01/14/2015] [Indexed: 01/21/2023] Open
Abstract
Introduction Cholangiocarcinoma (CCA) is an aggressive disease with limited effective treatment options. The PI3K/Akt/mTOR pathway represents an attractive therapeutic target due to its frequent dysregulation in CCA. MK2206, an allosteric Akt inhibitor, has been shown to reduce cellular proliferation in other cancers. We hypothesized that MK2206 mediated inhibition of Akt would impact CCA cellular viability. Study methods Post treatment with MK2206 (0-2 μM), cellular viability was assessed in two human CCA cell lines—CCLP-1 and SG231—using an MTT assay. Lysates from the MK2206 treated CCA cells were then examined for apoptotic marker expression levels using Western blot analysis. Additionally, the effect on cellular proliferation of MK2206 treatment on survivin depleted cells was determined. Results CCLP-1 and SG231 viability was significantly reduced at MK2206 concentrations of 0.5, 1, and 2 μM by approximately 44%, 53%, and 64% (CCLP-1; p = 0.01) and 32%, 32%, and 42% (SG231; p < 0.00005) respectively. Western analysis revealed a decrease in AKTSer473, while AKTThr308 expression was unchanged. In addition, cleaved PARP as well as survivin expression increased while pro-caspase 3 and 9 levels decreased with treatment. Depletion of survivin in CCLP-1 cells resulted in apoptosis as evidenced by increased cleaved PARP. In addition, survivin siRNA further enhanced the antitumor activity of MK2206. Conclusions This study demonstrates that by blocking phosphorylation of Akt at serine473, CCA cellular growth is reduced. The growth suppression appears to be mediated via apoptosis. Importantly, combination of survivin siRNA transfection and MK2206 treatment significantly decreased cell viability.
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Affiliation(s)
- Jacob M Wilson
- Medical College of Wisconsin, Translational and Biomedical Research Center, 8701 Watertown Plank Road, Milwaukee, WI 53226 USA
| | - Selvi Kunnimalaiyaan
- Medical College of Wisconsin, Translational and Biomedical Research Center, 8701 Watertown Plank Road, Milwaukee, WI 53226 USA
| | - Muthusamy Kunnimalaiyaan
- Medical College of Wisconsin, Translational and Biomedical Research Center, 8701 Watertown Plank Road, Milwaukee, WI 53226 USA
| | - T Clark Gamblin
- Department of Surgery, Division of Surgical Oncology, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226 USA
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Chaiteerakij R, Harmsen WS, Marrero CR, Aboelsoud MM, Ndzengue A, Kaiya J, Therneau TM, Sanchez W, Gores GJ, Roberts LR. A new clinically based staging system for perihilar cholangiocarcinoma. Am J Gastroenterol 2014; 109:1881-90. [PMID: 25384902 PMCID: PMC4341961 DOI: 10.1038/ajg.2014.327] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2014] [Revised: 08/01/2014] [Accepted: 08/01/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Current staging systems for perihilar cholangiocarcinoma (pCCA) are inadequate, as they are based on surgical pathology and therefore not relevant to unresectable patients. Clinical trials for potential targeted therapies for pCCA are hampered by the lack of an accurate, nonoperative staging system for predicting survival. We aimed at developing a clinical staging system for pCCA, which would be of prognostic relevance for all pCCA patients and help stratify patients for clinical trials. METHODS Clinical information at the time of pCCA diagnosis of 413 patients seen at Mayo Clinic, Rochester, MN between 2002 and 2010 was retrospectively analyzed. A survival predictive model was developed using Cox proportional hazards analysis. The performance of the staging system was compared with the current AJCC/UICC (the American Joint Committee on Cancer/the Union for International Cancer Control) 7th tumor-node-metastasis (TNM) staging system. RESULTS Eastern Cooperative Oncology Group (ECOG) status, tumor size and number, vascular encasement, lymph node and peritoneal metastasis and CA 19-9 level were grouped into a four-tier staging system. The median survivals of stages I, II, III, and IV patients were 48.6, 21.8, 8.6, and 2.8 months, with hazard ratios (95% confidence interval) of 1.0 (reference), 1.7 (1.1-2.6), 3.1 (2.0-4.7), and 8.7 (5.2-14.5), respectively (P<0.0001). This staging system had greater concordance statistics (standard error) than the TNM staging system (0.725 (0.018) vs. 0.614 (0.017)), indicating better performance in predicting survival. CONCLUSIONS This staging system, based on nonoperative information at the time of pCCA diagnosis, has excellent discriminatory power to classify patients into four prognostic stages. It could be useful to clinicians and for the design of clinical trials.
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Affiliation(s)
- Roongruedee Chaiteerakij
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, Minnesota, USA,Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - William S. Harmsen
- Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, and Mayo Clinic Cancer Center, Rochester, Minnesota, USA
| | - Carlos Romero Marrero
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, Minnesota, USA
| | - Mohammed M. Aboelsoud
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, Minnesota, USA
| | - Albert Ndzengue
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, Minnesota, USA
| | - Joseph Kaiya
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, Minnesota, USA
| | - Terry M. Therneau
- Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, and Mayo Clinic Cancer Center, Rochester, Minnesota, USA
| | - William Sanchez
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, Minnesota, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, Minnesota, USA
| | - Lewis R. Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center, Rochester, Minnesota, USA
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40
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Abstract
Optimal treatment of hilar cholangiocarcinoma depends on location of the cancer and extent of biliary and vascular involvement. Candidates for resection or transplantation must be evaluated and managed by a multidisciplinary team at a high-volume hepatobiliary center. Success requires absence of distant nodal or extrahepatic metastases and an adequate functional liver remnant with a negative ductal margin. Ipsilateral portal vein resection and reconstruction should be performed in patients with venous involvement. Neoadjuvant chemoradiation and liver transplantation is the best treatment option for patients with unresectable hilar cholangiocarcinoma without nodal or distant metastases and for patients with underlying chronic liver disease.
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Affiliation(s)
- Victor M Zaydfudim
- Department of Surgery, University of Virginia, 1300 Jefferson Park Avenue, Charlottesville, VA 22908, USA
| | - Charles B Rosen
- Division of Transplantation Surgery, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905, USA
| | - David M Nagorney
- Department of Surgery, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905, USA.
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41
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Abstract
Intrahepatic cholangiocarcinoma (ICC) is a rare tumor, with an increasing incidence worldwide and an overall poor prognosis. Symptoms are usually nonspecific, contributing to an advanced tumor stage at diagnosis. The staging system for ICC has recently been updated and is based on number of lesions, vascular invasion, and lymph node involvement. Complete surgical resection to negative margins remains the only potentially curable treatment for ICC. Gemcitabine-based adjuvant therapy can be offered based on limited data from patients with unresectable ICC. Overall 5-year survivals after resection range from 17% to 44%, with median survivals of 19 to 43 months.
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Patkowski W, Stankiewicz R, Grąt M, Krasnodębski M, Kornasiewicz O, Krawczyk M. Poor outcomes after liver transplantation in patients with incidental cholangiocarcinoma irrespective of tumor localization. Transplant Proc 2014; 46:2774-2776. [PMID: 25380915 DOI: 10.1016/j.transproceed.2014.09.057] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
INTRODUCTION After liver transplantation for cholangiocarcinoma (CCC), patients have a poor prognosis without use of specific therapeutic strategies. Accordingly, recipients with incidental CCC might have the highest risk of recurrent disease; however, sparse data on the long-term outcome of unselected patients with incidental CCC have been published. The aim of this study was to evaluate the post-transplantation outcomes of patients with incidental CCC with special focus on tumor localization. MATERIAL AND METHODS There were 11 primary liver transplantations in patients with incidental CCC of 1310 liver transplantation procedures performed between December 1994 and August 2013. All patients with incidental CCC received a chemotherapy regiment including gemcitabine/5 fluorouracil, doxorubicin, and mitomycin. The patients were switched from calcineurin inhibitors to mammalian target of rapamycin inhibitor-based immunosuppression shortly after CCC diagnosis. RESULTS Intra- and extrahepatic tumors were found in 6 and 5 patients, respectively. At median follow-up examination of 26.3 months there were 8 CCC recurrences and 7 patient deaths. Overall survival after liver transplantation for incidental CCC was 88.9% at 1 year, 44.4% at 2 years, and 14.8% at 3 years. The corresponding rates of recurrence-free survival were 45.7%, 45.7%, and 0.0%, respectively. Post-transplantation CCC recurrences were universal with 0% 3-year recurrence-free survival both in patients with intra- and extrahepatic tumors (P = .475). CONCLUSIONS Incidental CCC in liver transplantation is associated with poor outcomes irrespective of tumor localization. Introduction of new adjuvant multimodal treatment concepts is necessary to improve the prognosis for this subgroup of patients.
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Affiliation(s)
- W Patkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
| | - R Stankiewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - M Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - M Krasnodębski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - O Kornasiewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - M Krawczyk
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
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Qureshi K, Jesudoss R, Al-Osaimi AMS. The treatment of cholangiocarcinoma: a hepatologist's perspective. Curr Gastroenterol Rep 2014; 16:412. [PMID: 25183579 DOI: 10.1007/s11894-014-0412-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Cholangiocarcinoma (CCA) is a rare but lethal adenocarcinoma with cholangiocyte differentiation that arises within the biliary tree at variable locations. Curative options are available in the form of surgical resection and/or liver transplantation (LT) in early stage CCA; however, these are offered to a small fraction of patients as they are usually asymptomatic and remain undiagnosed. Primary sclerosing cholangitis (PSC) is a well-known risk factor of CCA, and cirrhosis, viral hepatitis, and metabolic syndrome are recently identified as risk factors of CCA. This emerging evidence places hepatologists in a vital position to diagnose, prognosticate, and manage CCA by planning treatment of each individual patient based on the stage and extent of malignancy. With appropriate selection of patients and the involvement of a multidisciplinary team, surgical resection of localized CCA, LT coupled with neoadjuvant chemoradiation for perihilar CCA, or locoregional or systemic chemotherapy and/or endoscopic interventions for advanced CCA can be offered.
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Affiliation(s)
- Kamran Qureshi
- Division of Hepatology, Department of Medicine, Temple University Health System, 3440 N. Broad Street, Kresge Building West, Philadelphia, PA, 19140, USA,
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Surgical resection of a malignant liver lesion: what the surgeon wants the radiologist to know. AJR Am J Roentgenol 2014; 203:W21-33. [PMID: 24951226 DOI: 10.2214/ajr.13.11701] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Hepatic malignancy is a common and lethal disease, whether due to a primary tumor or metastasis. There are numerous treatment options available depending on the stage of the disease and medical condition of the patient, including systemic chemotherapy, transcatheter embolization, thermal ablation, and surgical resection. In a subset of patients with liver malignancy, surgical resection can offer the best chance of long-term survival and potentially even cure. This article reviews the major indications and contraindications for resection, basic surgical techniques and terminology, key clinical and imaging preoperative workup, and pertinent interventional oncology procedures in the management of hepatic malignancy. CONCLUSION Diagnostic and interventional radiology plays an important role in the assessment and treatment of malignant hepatic lesions. Radiologists should be familiar with how surgeons select, work up, and treat candidates for liver resection to provide the most clinically valuable service.
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Zhang W, Yan LN. Perihilar cholangiocarcinoma: Current therapy. World J Gastrointest Pathophysiol 2014; 5:344-354. [PMID: 25133034 PMCID: PMC4133531 DOI: 10.4291/wjgp.v5.i3.344] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 04/11/2014] [Accepted: 06/11/2014] [Indexed: 02/06/2023] Open
Abstract
Perihilar cholangiocarcinoma, which is a rare primary malignancy, originates from the epithelial cells of the bile duct. Usually invading the periductal tissues and the lymph nodes, perihilar cholangiocarcinoma is commonly diagnosed in the advanced stage of the disease and has a dismal prognosis. Currently, complete hepatectomy is the primary therapy for curing this disease. Perioperative assessment and available surgical procedures can be considered for achieving a negative margin resection, which is associated with long-term survival and better quality of life. For patients with unresectable cholangiocarcinoma, several palliative treatments have been demonstrated to produce a better outcome; and liver transplantation for selected patients with perihilar cholangiocarcinoma is promising and desirable. However, the role of palliative treatments and liver transplantation was controversial and requires more evidence and substantial validity from multiple institutions. In this article, we summarize the data from multiple institutions and discuss the resectability, mortality, morbidity and outcome with different approaches.
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Barr Fritcher EG, Kipp BR, Halling KC, Clayton AC. FISHing for pancreatobiliary tract malignancy in endoscopic brushings enhances the sensitivity of routine cytology. Cytopathology 2014; 25:288-301. [PMID: 25073411 DOI: 10.1111/cyt.12170] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/15/2014] [Indexed: 12/21/2022]
Abstract
Pancreatobiliary tract carcinoma is a lethal disease with low survival rates and limited treatment options. Diagnosis is complicated by benign conditions that can mimic malignancy on radiological studies (e.g. primary sclerosing cholangitis or PSC) and the suboptimal sensitivity of endoscopic biopsy/brushings obtained by endoscopic retrograde cholangiopancreatography (ERCP). The detection of multiple chromosomal gains by fluorescence in situ hybridization (FISH), referred to as polysomy, has demonstrated improved sensitivity over routine cytological evaluation. The evaluation of brushings by both routine cytology and FISH in our cytopathology laboratory has been in clinical practice since 2003. Strong morphological and screening skills enable cytotechnologists to become proficient in the assessment of FISH slides, which translates into cost and time savings. Multiple reports from various institutions have demonstrated the utility of FISH for patients with and without PSC. The incorporation of routine cytology and FISH results into the management algorithm for patients under suspicion for pancreatobiliary malignancy is a testament to the clinical success of these cytological assays.
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Affiliation(s)
- E G Barr Fritcher
- Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, MN, USA
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Ravaioli M, Ercolani G, Neri F, Cescon M, Stacchini G, Gaudio MD, Cucchetti A, Pinna AD. Liver transplantation for hepatic tumors: A systematic review. World J Gastroenterol 2014; 20:5345-5352. [PMID: 24833864 PMCID: PMC4017049 DOI: 10.3748/wjg.v20.i18.5345] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2013] [Revised: 12/06/2013] [Accepted: 01/08/2014] [Indexed: 02/06/2023] Open
Abstract
Improvements in the medical and pharmacological management of liver transplantation (LT) recipients have led to a better long-term outcome and extension of the indications for this procedure. Liver tumors are relevant to LT; however, the use of LT to treat malignancies remains a debated issue because the high risk of recurrence. In this review we considered LT for hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), liver metastases (LM) and other rare tumors. We reviewed the literature, focusing on the past 10 years. The highly selected Milan criteria of LT for HCC (single nodule < 5 cm or up to 3 nodules < 3 cm) have been recently extended by a group from the University of S. Francisco (1 lesion < 6.5 cm or up to 3 lesions < 4.5 cm) with satisfying results in terms of recurrence-free survival and the “up-to-seven criteria”. Moreover, using these criteria, other transplant groups have recently developed downstaging protocols, including surgical or loco-regional treatments of HCC, which have increased the post-operative survival of recipients. CCA may be treated by LT in patients who cannot undergo liver resection because of underlying liver disease or for anatomical technical challenges. A well-defined protocol of chemoirradiation and staging laparotomy before LT has been developed by the Mayo Clinic, which has resulted in long term disease-free survival comparable to other indications. LT for LM has also been investigated by multicenter studies. It offers a real benefit for metastases from neuroendocrine tumors that are well differentiated and when a major extrahepatic resection is not required. If LT is an option in these selected cases, liver metastases from colorectal cancer is still a borderline indication because data concerning the disease-free survival are still lacking. Hepatoblastoma and hemangioendothelioma represent rare primary tumors for which LT is often the only possible and effective cure because of the frequent multifocal, intrahepatic nature of the disease. LT is a very promising procedure for both primary and secondary liver malignancies; however, it needs an accurate evaluation of the costs and benefits for each indication to balance the chances of cure with actual organ availability.
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49
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Sapisochin G, Rodríguez de Lope C, Gastaca M, Ortiz de Urbina J, Suarez MA, Santoyo J, Castroagudín JF, Varo E, López-Andujar R, Palacios F, Sanchez Antolín G, Perez B, Guiberteau A, Blanco G, González-Diéguez ML, Rodriguez M, Varona MA, Barrera MA, Fundora Y, Ferron JA, Ramos E, Fabregat J, Ciria R, Rufian S, Otero A, Vazquez MA, Pons JA, Parrilla P, Zozaya G, Herrero JI, Charco R, Bruix J. "Very early" intrahepatic cholangiocarcinoma in cirrhotic patients: should liver transplantation be reconsidered in these patients? Am J Transplant 2014; 14:660-7. [PMID: 24410861 DOI: 10.1111/ajt.12591] [Citation(s) in RCA: 124] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 11/12/2013] [Indexed: 01/25/2023]
Abstract
A retrospective cohort multicenter study was conducted to analyze the risk factors for tumor recurrence after liver transplantation (LT) in cirrhotic patients found to have an intrahepatic cholangiocarcinoma (iCCA) on pathology examination. We also aimed to ascertain whether there existed a subgroup of patients with single tumors ≤2 cm ("very early") in which results after LT can be acceptable. Twenty-nine patients comprised the study group, eight of whom had a "very early" iCCA (four of them incidentals). The risk of tumor recurrence was significantly associated with larger tumor size as well as larger tumor volume, microscopic vascular invasion and poor degree of differentiation. None of the patients in the "very early" iCCA subgroup presented tumor recurrence compared to 36.4% of those with single tumors >2 cm or multinodular tumors, p = 0.02. The 1-, 3- and 5-year actuarial survival of those in the "very early" iCCA subgroup was 100%, 73% and 73%, respectively. The present is the first multicenter attempt to ascertain the risk factors for tumor recurrence in cirrhotic patients found to have an iCCA on pathology examination. Cirrhotic patients with iCCA ≤2 cm achieved excellent 5-year survival, and validation of these findings by other groups may change the current exclusion of such patients from transplant programs.
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Affiliation(s)
- G Sapisochin
- Department of HBP Surgery and Transplantation, Hospital Universitario Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
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Abstract
The use of peroral endoscopy in the diagnosis of and therapy for biliary disorders has evolved immensely since the introduction of flexible fiberoptic endoscopes more than 50 years ago. Endoscopic retrograde cholangiopancreatography was introduced approximately a decade after flexible upper endoscopy and has evolved from a purely diagnostic procedure to almost exclusively a therapeutic procedure for managing biliary tract disorders. Endoscopic ultrasound, which continues to be a procedure of high diagnostic yield, is becoming a therapeutic modality for management of biliary diseases. This article discusses the diagnostic and therapeutic aspects of endoscopic retrograde cholangiopancreatography and endoscopic ultrasound for evaluation and treatment of biliary diseases.
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