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Wang R, Ren B, Zhang X, Liu B, Zhou W. Identification of AKTIP as a biomarker for fibrolamellar carcinoma using WGCNA and machine learning. 3 Biotech 2025; 15:181. [PMID: 40417661 PMCID: PMC12095112 DOI: 10.1007/s13205-025-04323-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 04/11/2025] [Indexed: 05/27/2025] Open
Abstract
Fibrolamellar carcinoma (FLC) is a rare form of liver carcinoma with limited diagnostic and therapeutic options. In this study, we utilized the GSE57727 and E-MTAB-1503 datasets, downloaded from GEO and ArrayExpress, respectively, to explore hub genes for FLC diagnosis and potential therapeutic agents. Through the integration of multiple machine learning approaches and drug sensitivity databases, we identified AKTIP as a potential diagnostic biomarker for FLC. AKTIP exhibited markedly elevated expression in FLC compared to non-FLC, demonstrating superior diagnostic and prognostic performance over other FLC-specific biomarkers. Four compounds (PI-103, BVT-948, Digitoxigenin, and SB-218078) were identified as potential therapeutic agents targeting AKTIP. Molecular docking analysis revealed strong binding affinities of these compounds to AKTIP, and molecular dynamics simulations further validated the reliability and rationality of the molecular docking results. Pan-cancer analysis indicated that AKTIP expression varies across different tissues and is significantly associated with patient prognosis. qRT-PCR analysis confirmed that AKTIP mRNA levels were markedly overexpressed in normal liver epithelial cells compared to human hepatocellular carcinoma cell lines. In conclusion, AKTIP was successfully identified as a diagnostic and prognostic biomarker for FLC, and four compounds were proposed as potential therapeutic agents. This study uncovers new perspectives on diagnosing and managing of this rare type of liver carcinoma, offering promising avenues for future research and clinical applications. Supplementary Information The online version contains supplementary material available at 10.1007/s13205-025-04323-4.
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Affiliation(s)
- Rui Wang
- The Second Clinical Medical School, Lanzhou University, Lanzhou, 730030 China
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, 730030 China
| | - Bo Ren
- The Second Clinical Medical School, Lanzhou University, Lanzhou, 730030 China
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, 730030 China
| | - Xijie Zhang
- The Second Clinical Medical School, Lanzhou University, Lanzhou, 730030 China
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, 730030 China
| | - Bo Liu
- The Second Clinical Medical School, Lanzhou University, Lanzhou, 730030 China
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, 730030 China
| | - Wence Zhou
- The Second Clinical Medical School, Lanzhou University, Lanzhou, 730030 China
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, 730030 China
- Gansu Province Hepatobiliary Pancreatic Disease Precision Diagnosis and Treatment Engineering Research Center, Lanzhou, 730030 China
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2
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Melehy A, Agopian VG. Role of Liver Transplant in Primary and Secondary Liver Malignancies. Clin Liver Dis 2025; 29:217-234. [PMID: 40287268 DOI: 10.1016/j.cld.2024.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2025]
Abstract
Hepatocellular carcinoma (HCC) and cholangiocarcinoma are the primary hepatic malignancies with established pathways to transplantation and model for end-stage liver disease (MELD) exception points. Other tumors managed with liver transplantation (LT) include hepatic epithelioid hemangioendothelioma and fibrolamellar HCC. LT for metastatic neuroendocrine tumor has been established with patient selection criteria and a path to MELD exception points. Additionally, recent data on LT for patients with unresectable hepatic colorectal metastases demonstrate increasingly encouraging initial results.
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Affiliation(s)
- Andrew Melehy
- Department of Surgery, Dumont-UCLA Transplant and Liver Cancer Centers, David Geffen School of Medicine at University of California, Los Angeles, CA, USA
| | - Vatche G Agopian
- Division of Liver and Pancreas Transplantation, Department of Surgery, Dumont-UCLA Transplant and Liver Cancer Centers, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
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3
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Ye-Tran X, Bouattour M, Fresneau B, Turpin A, Perret A, Vitellius C, Coriat R, Blanc JF, Lequoy M, Regnault H, Pietrasz D, Sefrioui D, Lecomte T, Moati E, Caliez O, Nguyen-Khac E, Walter T, Hautefeuille V. Response to systemic treatments and survival of fibrolamellar carcinomas: An AGEO-SFCE French multicenter retrospective cohort. Dig Liver Dis 2025:S1590-8658(25)00328-7. [PMID: 40316454 DOI: 10.1016/j.dld.2025.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 02/13/2025] [Accepted: 04/07/2025] [Indexed: 05/04/2025]
Abstract
INTRODUCTION Fibrolamellar carcinomas (FLC) are rare and predominantly advanced hepatic malignancies, lacking a clear consensus on anti-tumor treatments (ATT). The primary objective of the study was to determine whether any ATT appeared to give favorable outcomes in terms of morphological objective response (ORR) and disease control (DCR) rate according to RECIST 1.1 criteria. PATIENTS AND METHODS This retrospective multicentric French cohort from 14 centers included 44 patients with histologically proven FLC who received at least one ATT (chemotherapy and/or tyrosine kinase inhibitors, TKI) and underwent at least one morphological evaluation. . RESULTS A total of 40 anti-tumor responses were analyzed after a first line treatment. No complete response was observed, with an ORR in 13 % of cases, a DCR in 55 % of cases and 45 % of disease progression. GEMOX regimen (n = 9) showed an ORR of 11 % and a DCR of 33 %; the combination of doxorubicin and platinum-based chemotherapy (n = 6) achieved an ORR of 33 % and a DCR of 83 %. For TKI, sorafenib (n = 10) and sunitinib (n = 3), there was no objective response, with a DCR of 40 % and 33 % respectively. The median and the 5-years overall survival were 3.3 years and 35 % (95 %CI=[0.23-0.54]) respectively. CONCLUSION FLC have a poor prognosis; ATT show mild response rate. Further approaches and personalized medicine seem to be an unmet need for patients with FLC and new treatments should be urgently developed.
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Affiliation(s)
- Xixi Ye-Tran
- Gastroenterology Department, Grand Hôpital de l'Est Francilien (GHEF), Meaux, France
| | - Mohamed Bouattour
- Liver Cancer Unit, Assistance Publique - Hôpitaux de Paris, Beaujon University Hospital, Clichy, France
| | - Brice Fresneau
- Gustave Roussy, Department of Children and Adolescents Oncology, Villejuif, F-94805, France
| | - Anthony Turpin
- Medical Oncology - Lille University Hospital - Lille, France
| | - Audrey Perret
- Medical Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Carole Vitellius
- Hepato-Gastroenterology Department, University Hospital, Angers, France
| | - Romain Coriat
- Department of gastroenterology and endoscopy, Hôpital Cochin, Université Paris Cité, Paris, France
| | - Jean Frederic Blanc
- Department of Digestive Oncology, Hôpital Haut-Lévêque, Bordeaux University Hospital, Pessac, France
| | - Marie Lequoy
- Department of Hepatology, AP-HP, Saint-Antoine Hospital, F-75012, Paris, France
| | - Hélène Regnault
- Department of Hepatology, Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Créteil, France
| | - Daniel Pietrasz
- Department of Digestive, Oncological, and Transplant Surgery, Paul Brousse Hospital, Paris-Saclay University, Villejuif, France
| | - David Sefrioui
- Department of Gastroenterology, Digestive Oncology Unit, Rouen University Hospital, Rouen, France
| | - Thierry Lecomte
- Hepato-gastroenterology and Digestive Oncology, Tours University Hospital, Tours, France
| | - Emilie Moati
- Department of Gastroenterology and Digestive Oncology, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, Institut du Cancer Paris Carpem, Paris, France
| | - Olivier Caliez
- Department of Hepato-gastroenterology, Assistance Publique, Hôpitaux de Paris, Pitié Salpêtrière University Hospital, Paris, France
| | - Eric Nguyen-Khac
- Hepato-gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France
| | - Thomas Walter
- Gastroenterology and Digestive Oncology, Edouard Herriot University Hospital, Hospices Civils de Lyon, Lyon, France
| | - Vincent Hautefeuille
- Hepato-gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France.
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Abou-Alfa GK, Meyer T, Do RKG, Piha-Paul SA, Light JS, Sherrin S, Yaqubie A, O’Neill AC, Harding JJ, Al-Rajabi R, Denlinger CS, Cano P, Cornelius AS, O’Reilly EM, DiPrimeo D, Eli LD, Gordan JD, Solit DB. Neratinib Alone or in Combination with Immune Checkpoint Inhibitors with or without Mammalian Target of Rapamycin Inhibitors in Patients with Fibrolamellar Carcinoma. Liver Cancer 2025; 14:58-67. [PMID: 40144471 PMCID: PMC11936434 DOI: 10.1159/000540290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 07/05/2024] [Indexed: 03/28/2025] Open
Abstract
Introduction Fibrolamellar carcinoma (FLC) displays upregulation of several oncogenes, including HER2, and multiple immune-suppressive mechanisms. We investigated the efficacy and safety of the pan-HER tyrosine kinase inhibitor neratinib as monotherapy (SUMMIT phase 2 basket study) or with immune checkpoint and/or mammalian target of rapamycin (mTOR) inhibitors (compassionate-use program) in patients with FLC. Methods Patients received neratinib 240 mg/day orally in SUMMIT, or as doublet or triplet combinations with pembrolizumab 2 mg/kg intravenously every 3 weeks, nivolumab 240 mg intravenously every 2 weeks, everolimus 7.5 mg/day orally, or sunitinib 37.5 mg/day orally under compassionate use. The primary endpoint in SUMMIT was objective response rate; safety was a secondary endpoint. Results Fifteen patients with FLC received neratinib monotherapy in SUMMIT. The objective response rate was 5% (95% confidence interval [CI]: 0-21.8) and the disease control rate was 13.3% (95% CI: 1.7-40.5). Upon progression, five had added immune checkpoint inhibitors with or without everolimus or sunitinib. Two additional patients received neratinib-based combinations outside of SUMMIT, for a total of 17 neratinib-treated patients. One patient who received neratinib plus pembrolizumab had a confirmed partial response, one treated with neratinib plus everolimus had stable disease lasting 6 months, and one who received neratinib plus pembrolizumab plus sunitinib had stable disease lasting 16 months. Grade 3/4 adverse events with neratinib monotherapy occurred in 10 (66.7%)/2 (13.3%) patients, respectively. Grade 3 adverse events with neratinib-based combinations were hyperglycemia (n = 1; neratinib plus pembrolizumab), hepatic failure, and anaphylaxis (n = 1 each, neratinib plus pembrolizumab plus everolimus). There were no grade 4 adverse events with combination therapy. Conclusion In patients with FLC, single-agent neratinib had limited efficacy, but clinical benefit was observed with neratinib in combination with immunotherapy and/or mTOR-targeted agents.
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Affiliation(s)
- Ghassan K. Abou-Alfa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA
- Department of Medicine, Medical School, Trinity College Dublin University, Dublin, Ireland
| | - Tim Meyer
- Department of Oncology, Royal Free Hospital, London, UK
- Department of Oncology, UCL Cancer Institute, University College London, London, UK
| | - Richard Kinh Gian Do
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA
| | - Sarina A. Piha-Paul
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Joseph S. Light
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Scott Sherrin
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Amin Yaqubie
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - James J. Harding
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA
| | - Raed Al-Rajabi
- Department of Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Crystal S. Denlinger
- Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Pablo Cano
- Department of Hematology/Oncology, Sudbury Regional Hospital, Sudbury, ON, Canada
| | - Albert S. Cornelius
- Department of Medicine, Helen DeVos Children’s Hospital, Grand Rapids, MI, USA
| | - Eileen M. O’Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA
| | | | - Lisa D. Eli
- Translational Medicine and Biometrics, Puma Biotechnology Inc., Los Angeles, CA, USA
| | - John D. Gordan
- Division of Hematology/Oncology, CSF GI Medical Oncology, San Francisco, CA, USA
| | - David B. Solit
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA
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5
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Allkushi E, Wehrle CJ, Kim J, Khalil M, Kwon DCH, Fujiki M, Pinna AD, Miller C, Schlegel A, Aucejo F, Hashimoto K, Pita A. Expanding Indications in Transplant Oncology. Cancers (Basel) 2025; 17:773. [PMID: 40075625 PMCID: PMC11898796 DOI: 10.3390/cancers17050773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 02/16/2025] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
Liver transplantation is aptly described as the only curative treatment for cirrhosis and cirrhosis with co-morbid hepatocellular carcinoma (HCC). Its utility in the management of various other primary and secondary liver cancers is gaining traction rapidly, with more thorough assessments on broader populations continuing to emerge. Most prominently, this includes colorectal cancer liver metastasis (CRLM), cholangiocarcinoma (CCA), neuroendocrine tumors (NETs), and more. Furthermore, despite being a well described treatment for HCC for many years, growing evidence supports a change in oncological strategy for HCC, with broadened selection criteria and more advanced systemic and locoregional therapies available. Our review aims to describe the evidence supporting the expansion of indications and selection criteria for liver transplantation in various oncologic indications of primary and secondary liver tumors.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Alejandro Pita
- Transplantation Center, Department of Liver Transplantation, Cleveland Clinic, Cleveland, OH 44195, USA (C.J.W.); (J.K.); (M.K.); (D.C.H.K.); (M.F.); (A.D.P.); (A.S.); (K.H.)
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6
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Farghli AR, Chan M, Sherman MS, Dickerson LK, Shui B, Nukaya M, Stephanou A, Ma RK, Pepe-Mooney BJ, Smith CJ, Long D, Munn PR, McNairn A, Grenier JK, Karski M, Ronnekleiv-Kelly SM, Pillarisetty VG, Goessling W, Gujral TS, Vakili K, Sethupathy P. Single-cell multi-omic analysis of fibrolamellar carcinoma reveals rewired cell-to-cell communication patterns and unique vulnerabilities. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.11.627911. [PMID: 39713360 PMCID: PMC11661214 DOI: 10.1101/2024.12.11.627911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
Fibrolamellar carcinoma (FLC) is a rare malignancy disproportionately affecting adolescents and young adults with no standard of care. FLC is characterized by thick stroma, which has long suggested an important role of the tumor microenvironment. Over the past decade, several studies have revealed aberrant markers and pathways in FLC. However, a significant drawback of these efforts is that they were conducted on bulk tumor samples. Consequently, identities and roles of distinct cell types within the tumor milieu, and the patterns of intercellular communication, have yet to be explored. In this study we unveil cell-type specific gene signatures, transcription factor networks, and super-enhancers in FLC using a multi-omics strategy that leverages both single-nucleus ATAC-seq and single-nucleus RNA-seq. We also infer completely rewired cell-to-cell communication patterns in FLC including signaling mediated by SPP1-CD44, MIF-ACKR3, GDF15-TGFBR2, and FGF7-FGFR. Finally, we validate findings with loss-of-function studies in several models including patient tissue slices, identifying vulnerabilities that merit further investigation as candidate therapeutic targets in FLC.
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7
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Apumayta ED, Kahlam A, Ruiz EF. Fibrolamellar Carcinoma: A Rare Liver Neoplasm. Cureus 2024; 16:e59006. [PMID: 38800256 PMCID: PMC11127726 DOI: 10.7759/cureus.59006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2024] [Indexed: 05/29/2024] Open
Abstract
Fibrolamellar carcinoma is a rare liver tumor, with most cases arising in people younger than 40 years of age. We present a case series of five patients with histological confirmation of fibrolamellar carcinoma who had liver resection as the primary treatment. The median age of diagnosis was 24 years with nonspecific clinical manifestations in otherwise healthy patients. Alpha-fetoprotein levels were widely variable. Patients had classical imaging, macroscopic, and microscopic findings. Most of our patients underwent a hemihepatectomy and 60% recurred after the first year.
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Affiliation(s)
- Elily D Apumayta
- Department of Abdominal Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima, PER
| | - Aaron Kahlam
- Department of Internal Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Eloy F Ruiz
- Department of Internal Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
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8
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Hackenbruch C, Bauer J, Heitmann JS, Maringer Y, Nelde A, Denk M, Zieschang L, Kammer C, Federmann B, Jung S, Martus P, Malek NP, Nikolaou K, Salih HR, Bitzer M, Walz JS. FusionVAC22_01: a phase I clinical trial evaluating a DNAJB1-PRKACA fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion. Front Oncol 2024; 14:1367450. [PMID: 38606105 PMCID: PMC11007196 DOI: 10.3389/fonc.2024.1367450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 03/13/2024] [Indexed: 04/13/2024] Open
Abstract
The DNAJB1-PRKACA fusion transcript was identified as the oncogenic driver of tumor pathogenesis in fibrolamellar hepatocellular carcinoma (FL-HCC), also known as fibrolamellar carcinoma (FLC), as well as in other tumor entities, thus representing a broad target for novel treatment in multiple cancer entities. FL-HCC is a rare primary liver tumor with a 5-year survival rate of only 45%, which typically affects young patients with no underlying primary liver disease. Surgical resection is the only curative treatment option if no metastases are present at diagnosis. There is no standard of care for systemic therapy. Peptide-based vaccines represent a low side-effect approach relying on specific immune recognition of tumor-associated human leucocyte antigen (HLA) presented peptides. The induction (priming) of tumor-specific T-cell responses against neoepitopes derived from gene fusion transcripts by peptide-vaccination combined with expansion of the immune response and optimization of immune function within the tumor microenvironment achieved by immune-checkpoint-inhibition (ICI) has the potential to improve response rates and durability of responses in malignant diseases. The phase I clinical trial FusionVAC22_01 will enroll patients with FL-HCC or other cancer entities carrying the DNAJB1-PRKACA fusion transcript that are locally advanced or metastatic. Two doses of the DNAJB1-PRKACA fusion-based neoepitope vaccine Fusion-VAC-XS15 will be applied subcutaneously (s.c.) with a 4-week interval in combination with the anti-programmed cell death-ligand 1 (PD-L1) antibody atezolizumab starting at day 15 after the first vaccination. Anti-PD-L1 will be applied every 4 weeks until end of the 54-week treatment phase or until disease progression or other reason for study termination. Thereafter, patients will enter a 6 months follow-up period. The clinical trial reported here was approved by the Ethics Committee II of the University of Heidelberg (Medical faculty of Mannheim) and the Paul-Ehrlich-Institute (P-00540). Clinical trial results will be published in peer-reviewed journals. Trial registration numbers EU CT Number: 2022-502869-17-01 and ClinicalTrials.gov Registry (NCT05937295).
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Affiliation(s)
- Christopher Hackenbruch
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
- Department of Peptide-based Immunotherapy, Institute of Immunology, University and University Hospital Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
| | - Jens Bauer
- Department of Peptide-based Immunotherapy, Institute of Immunology, University and University Hospital Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
| | - Jonas S. Heitmann
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
- Department of Peptide-based Immunotherapy, Institute of Immunology, University and University Hospital Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
| | - Yacine Maringer
- Department of Peptide-based Immunotherapy, Institute of Immunology, University and University Hospital Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
| | - Annika Nelde
- Department of Peptide-based Immunotherapy, Institute of Immunology, University and University Hospital Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
| | - Monika Denk
- Department of Peptide-based Immunotherapy, Institute of Immunology, University and University Hospital Tübingen, Tübingen, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), partner site Tübingen, Tübingen, Germany
| | - Lisa Zieschang
- Department of Peptide-based Immunotherapy, Institute of Immunology, University and University Hospital Tübingen, Tübingen, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), partner site Tübingen, Tübingen, Germany
| | - Christine Kammer
- Department of Peptide-based Immunotherapy, Institute of Immunology, University and University Hospital Tübingen, Tübingen, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), partner site Tübingen, Tübingen, Germany
| | - Birgit Federmann
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
- Department of Peptide-based Immunotherapy, Institute of Immunology, University and University Hospital Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
| | - Susanne Jung
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
- Department of Peptide-based Immunotherapy, Institute of Immunology, University and University Hospital Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
| | - Peter Martus
- Institute for Medical Biometrics and Clinical Epidemiology, University Hospital Tübingen, Tübingen, Germany
| | - Nisar P. Malek
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), partner site Tübingen, Tübingen, Germany
- Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany
- Center for Personalized Medicine, University of Tübingen, Tübingen, Germany
- The M3 Research Institute, University of Tübingen, Tübingen, Germany
| | - Konstantin Nikolaou
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), partner site Tübingen, Tübingen, Germany
- Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Helmut R. Salih
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
| | - Michael Bitzer
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), partner site Tübingen, Tübingen, Germany
- Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany
- Center for Personalized Medicine, University of Tübingen, Tübingen, Germany
| | - Juliane S. Walz
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
- Department of Peptide-based Immunotherapy, Institute of Immunology, University and University Hospital Tübingen, Tübingen, Germany
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), partner site Tübingen, Tübingen, Germany
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9
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Hsiao CY, Ren Y, Chng E, Tai D, Huang KW. Potential of Using qFibrosis Analysis to Predict Recurrent and Survival Outcome of Patients with Hepatocellular Carcinoma after Hepatic Resection. Oncology 2024; 102:924-934. [PMID: 38527441 PMCID: PMC11548100 DOI: 10.1159/000538456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 02/27/2024] [Indexed: 03/27/2024]
Abstract
BACKGROUND There remains a lack of studies addressing the stromal background and fibrosis features and their prognostic value in liver cancer. qFibrosis can identify, quantify, and visualize the fibrosis features in biopsy samples. In this study, we aim to demonstrate the prognostic value of histological features by using qFibrosis analysis in liver cancer patients. METHODS Liver specimens from 201 patients with hepatocellular carcinoma (HCC) who underwent curative resection were imaged and assessed using qFibrosis system and generated a total of 33 and 156 collagen parameters from tumor part and non-tumor liver tissue, respectively. We used these collagen parameters on patients to build two combined indexes, RFS index and OS index, in order to differentiate patients with early recurrence and early death, respectively. The models were validated using the leave-one-out method. RESULTS Both combined indexes had significant prediction value for patients' outcome. The RFS index of 0.52 well differentiates patients with early recurrence (p < 0.001), and the OS index of 0.73 well differentiates patients with early death during follow-up (p = 0.02). CONCLUSIONS Combined index calculated with qFibrosis from a digital readout of the fibrotic status of peri-tumor liver specimen in patients with HCC has prediction values for their disease and survival outcomes. These results demonstrated the potential to transform histopathological features into quantifiable data that could be used to correlate with clinical outcome.
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Affiliation(s)
- Chih-Yang Hsiao
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan,
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan,
- Department of Traumatology, National Taiwan University Hospital, Taipei, Taiwan,
| | - Yayun Ren
- HistoIndex, Pte Ltd, Singapore, Singapore
| | | | - Dean Tai
- HistoIndex, Pte Ltd, Singapore, Singapore
| | - Kai-Wen Huang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
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10
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Kirk AM, Crawford JC, Chou CH, Guy C, Pandey K, Kozlik T, Shah RK, Chung S, Nguyen P, Zhang X, Wang J, Bell M, Mettelman RC, Allen EK, Pogorelyy MV, Kim H, Minervina AA, Awad W, Bajracharya R, White T, Long D, Gordon B, Morrison M, Glazer ES, Murphy AJ, Jiang Y, Fitzpatrick EA, Yarchoan M, Sethupathy P, Croft NP, Purcell AW, Federico SM, Stewart E, Gottschalk S, Zamora AE, DeRenzo C, Strome SE, Thomas PG. DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma. Cell Rep Med 2024; 5:101469. [PMID: 38508137 PMCID: PMC10983114 DOI: 10.1016/j.xcrm.2024.101469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 11/29/2023] [Accepted: 02/20/2024] [Indexed: 03/22/2024]
Abstract
Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in FLC is its driver mutation, a conserved DNAJB1-PRKACA gene fusion that could be an ideal target neoantigen for immunotherapy. In this study, we aim to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) for use in cellular immunotherapies. We observe that fusion-specific CD8 T cells are rare and that FLC patient TCR repertoires lack large clusters of related TCR sequences characteristic of potent antigen-specific responses, potentially explaining why endogenous immune responses are insufficient to clear FLC tumors. Nevertheless, we define two functional fusion-specific TCRs, one of which has strong anti-tumor activity in vivo. Together, our results provide insights into the fragmented nature of neoantigen-specific repertoires in humans and indicate routes for clinical development of successful immunotherapies for FLC.
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Affiliation(s)
- Allison M Kirk
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Jeremy Chase Crawford
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Ching-Heng Chou
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Cliff Guy
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Kirti Pandey
- Department of Biochemistry and Molecular Biology and Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
| | - Tanya Kozlik
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Ravi K Shah
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Shanzou Chung
- Department of Biochemistry and Molecular Biology and Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
| | - Phuong Nguyen
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Xiaoyu Zhang
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Jin Wang
- Department of Microbiology, Immunology, and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Matthew Bell
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Robert C Mettelman
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - E Kaitlynn Allen
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Mikhail V Pogorelyy
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Hyunjin Kim
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Anastasia A Minervina
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Walid Awad
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Resha Bajracharya
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Toni White
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Donald Long
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14850, USA
| | - Brittney Gordon
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Michelle Morrison
- Center for Cancer Research, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Evan S Glazer
- Center for Cancer Research, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; Department of Surgery, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Andrew J Murphy
- Department of Surgery, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Yixing Jiang
- Department of Medical Oncology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Elizabeth A Fitzpatrick
- Department of Microbiology, Immunology, and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Mark Yarchoan
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Praveen Sethupathy
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14850, USA
| | - Nathan P Croft
- Department of Biochemistry and Molecular Biology and Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
| | - Anthony W Purcell
- Department of Biochemistry and Molecular Biology and Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
| | - Sara M Federico
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Elizabeth Stewart
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Stephen Gottschalk
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Anthony E Zamora
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Christopher DeRenzo
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Scott E Strome
- College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
| | - Paul G Thomas
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
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11
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Ma RK, Tsai PY, Farghli AR, Shumway A, Kanke M, Gordan JD, Gujral TS, Vakili K, Nukaya M, Noetzli L, Ronnekleiv-Kelly S, Broom W, Barrow J, Sethupathy P. DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma. PLoS Genet 2024; 20:e1011216. [PMID: 38512964 PMCID: PMC11020935 DOI: 10.1371/journal.pgen.1011216] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 04/16/2024] [Accepted: 03/08/2024] [Indexed: 03/23/2024] Open
Abstract
Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene DNAJB1-PRKACA (DP fusion), but clinical inhibitors are not yet developed and it is critical to identify downstream mediators of FLC pathogenesis. Here, we identify long noncoding RNA LINC00473 among the most highly upregulated genes in FLC tumors and determine that it is strongly suppressed by RNAi-mediated inhibition of the DP fusion in FLC tumor epithelial cells. We show by loss- and gain-of-function studies that LINC00473 suppresses apoptosis, increases the expression of FLC marker genes, and promotes FLC growth in cell-based and in vivo disease models. Mechanistically, LINC00473 plays an important role in promoting glycolysis and altering mitochondrial activity. Specifically, LINC00473 knockdown leads to increased spare respiratory capacity, which indicates mitochondrial fitness. Overall, we propose that LINC00473 could be a viable target for this devastating disease.
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Affiliation(s)
- Rosanna K. Ma
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
| | - Pei-Yin Tsai
- Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States of America
| | - Alaa R. Farghli
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
| | - Alexandria Shumway
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
| | - Matt Kanke
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
| | - John D. Gordan
- Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, United States of America
| | - Taranjit S. Gujral
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America
| | - Khashayar Vakili
- Department of Surgery, Boston Children’s Hospital, Boston, Massachusetts, United States of America
| | - Manabu Nukaya
- Department of Surgery, Division of Surgical Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Leila Noetzli
- Alnylam Pharmaceuticals, Cambridge, Massachusetts, United States of America
| | - Sean Ronnekleiv-Kelly
- Department of Surgery, Division of Surgical Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Wendy Broom
- Alnylam Pharmaceuticals, Cambridge, Massachusetts, United States of America
| | - Joeva Barrow
- Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States of America
| | - Praveen Sethupathy
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
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12
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Melehy A, Agopian V. Treating rare tumors with liver transplantation. Curr Opin Organ Transplant 2024; 29:30-36. [PMID: 37851086 DOI: 10.1097/mot.0000000000001118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2023]
Abstract
PURPOSE OF REVIEW The success of liver transplantation (LT) in treating unresectable hepatocellular carcinoma (HCC) has resulted in interest in LT for other oncologic conditions. Here, we discuss the role of LT for rare oncologic indications including metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs), hepatic epitheliod hemangioendothelioma (HEHE), fibrolamellar hepatocellular carcinoma (FLC), and hepatic angiosarcoma (HAS). RECENT FINDINGS Conditions reviewed have been documented indications for LT in the available literature. We summarize the experience of LT for these indications and proposed management guidelines. SUMMARY GEP-NETs with isolated metastases to the liver can be treated with LT with excellent long-term outcomes (10-year survival 88%) if strict selection criteria are used (low-intermediate grade, Ki-67% < 20%, complete resection of primary tumor, stable disease for 6 months, <50% hepatic involvement). HEHE is a rare hepatic tumor for which LT can be performed with reported 10-year survival around 70%. FLC is a distinct clinical entity to HCC and is optimally treated with surgical resection though experience with LT is described in observational series (5-year survival 50%, recurrence in 10%). HAS is a rapidly progressive tumor with a dismal prognosis with or without treatment, including LT.
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Affiliation(s)
- Andrew Melehy
- Dumont-UCLA Transplant and Liver Cancer Centers, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, California, USA
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13
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Huang S, Song JL, Li B, Yi PS, Yang J. Should lymphadenectomy performed routinely in patients with primary intrahepatic cholangiocarcinoma undergoing curative hepatectomy? A retrospective cohort study with propensity-score matching analysis. BMC Surg 2023; 23:364. [PMID: 38036995 PMCID: PMC10688469 DOI: 10.1186/s12893-023-02255-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 11/02/2023] [Indexed: 12/02/2023] Open
Abstract
BACKGROUND The benefit of routine lymphadenectomy (LD) in improving outcomes for patients with primary intrahepatic cholangiocarcinoma (ICC) undergoing curative hepatectomy remains unclear. MATERIALS AND METHODS This study enrolled 269 consecutive patients who underwent liver resection for primary ICC from January 2009 to July 2020 in West China Hospital. The association of the nodal status with disease-free survival (DFS) and overall survival (OS) was analyzed using the Cox proportional hazards model and 1:1 propensity score matching (PSM) analysis. RESULTS Seventy-five (27.9%) patients underwent curative liver resection combined with LD (LD+ group), while 194 (72.1%) patients received curative liver resection without LD (LD- group and Nx group). Among the LD+ group, metastatic disease was present in 36 patients (48%, N1 group) and absent in 39 patients (N0 group). During the follow-up period, 116 patients (43.1%) experienced tumor recurrence and 101 patients (37.5%) died due to recurrence. Multivariate analysis revealed that lymph node metastasis (N1, HR 3.682, 95% CI 1.949-6.957, p < 0.001) was associated with worse OS, while LD+ status (HR 0.504, 95% CI 0.298-0.853, p = 0.011) was associated with improved OS. Adjuvant therapy was a protective factor for both DFS (HR 0.602, 95% CI, 0.447-0.810, p = 0.001) and OS (HR 0.683, 95% CI 0.484-0.963, p = 0.030). After 1:1 PSM, the LD+ patients (n = 74) displayed similar 1-, 3- and 5-year DFS rates (40.0, 7.9 and 7.9% vs. 29.0, 13.7 and 13.7%, p = 0.741) and OS rates (56.0, 26.6 and 22.2% vs. 58.9, 25.6, and 16.4%, p = 0.644) to the LD- patients (n = 74). Additionally, among the 75 LD+ patients, 48 patients underwent hepatic hilar lymphadenectomy (HHL), and 27 patients underwent extended hepatic hilar lymphadenectomy (EHL). Both DFS (p = 0.504) and OS (p = 0.215) were similar between the HHL and EHL groups. CONCLUSION Routine LD and adjuvant therapy may contribute to improved OS according to the crude analysis. LD could provide accurate staging without excessive risk and guide adjuvant therapy based on the tumor stage, potentially resulting in better survival. These results suggest that a routine LD should be considered during curative hepatectomy for ICC.
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Affiliation(s)
- Shan Huang
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Sichuan Province, Chengdu, 610072, China
| | - Jiu-Lin Song
- Department of Pediatric Surgery, West China Hospital of Sichuan University, Sichuan Province, Chengdu, 610041, China
- Department of Liver Transplantation Center, West China Hospital of Sichuan University, Sichuan Province, Chengdu, 610041, China
| | - Bo Li
- Department of Vascular Surgery, West China Hospital of Sichuan University, Sichuan Province, Chengdu, 610041, China
| | - Peng-Sheng Yi
- Affiliated Hospital of North Sichuan Medical College, Sichuan Province, the Nanchong City, China
| | - Jian Yang
- Department of Liver Transplantation Center, West China Hospital of Sichuan University, Sichuan Province, Chengdu, 610041, China.
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14
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Da Fonseca LG, Yamamoto VJ, Trinconi Cunha M, Torre GS, Araujo RLC, Fonseca GM, Chen ATC, Chagas AL, Herman P, Alves VAF, Carrilho FJ. Treatment Outcomes in Patients with Advanced Fibrolamellar Hepatocellular Carcinoma Under Systemic Treatment: Analysis of Clinical Characteristics, Management, and Radiomics. J Hepatocell Carcinoma 2023; 10:1923-1933. [PMID: 37933267 PMCID: PMC10625783 DOI: 10.2147/jhc.s428741] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 10/24/2023] [Indexed: 11/08/2023] Open
Abstract
Purpose Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare primary liver malignancy often diagnosed at advanced stages. While there are limited data on the efficacy of specific agents, we aim to report outcomes of patients treated with systemic therapies and explore prognostic factors. Patients and Methods Medical records of patients treated between 2010 and 2022 were reviewed. Treatments were defined after multidisciplinary assessment. Descriptive statistics were used for baseline demographics. Time-to-event outcomes were estimated using the Kaplan-Meier method, compared by log-rank and adjusted by a regression model. Radiomic features (including size, shape, and texture) of the primary lesion were extracted and dimensionality reduced. An unsupervised Gaussian Mixture Model (GMM) clustering was performed, and survival was compared between clusters. Results We identified 23 patients: 12 males, with a median age of 23.6 years. At diagnosis, 82.6% had metastases, most frequently to the lungs (39.1%), lymph nodes (39.1%), and peritoneum (21.7%). Patients received a median of three lines (1-8) of treatment, including different regimens. Sorafenib (39.1%), capecitabine (30.4%), and capecitabine/interferon (13%) were the most used first-line regimens. The median time-to-failure was 3.8 months (95% CI: 3.2-8.7). Capecitabine + interferon (42.1%) and platinum combinations (39.1%) were the most used second-line regimens, with a time-to-failure of 3.5 months (95% CI: 1.5-11.6). Median overall survival was 26.7 months (95% CI: 15.1-40.4). A high baseline neutrophil-to-lymphocyte ratio (NLR) was associated with worse survival (p=0.02). Radiomic features identified three clusters, with one cluster (n=6) having better survival (40.4 vs 22.6 months, p=0.039). Tumor sphericity in the arterial phase was the most relevant characteristic associated with a better prognosis (accuracy=0.93). Conclusion FLHCC has unique features compared to conventional HCC, including young onset, gender balance, and absence of hepatopathy. Systemic therapies can provide encouraging survival, but lack of uniformity precludes defining a preferable regimen. Radiomics and NLR were suggested to correlate with prognosis and warrant further validation.
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Affiliation(s)
- Leonardo G Da Fonseca
- Department of Medical Oncology, ICESP - Instituto do Cancer DO Estado de Sao Paulo, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Victor Junji Yamamoto
- Department of Medical Oncology, ICESP - Instituto do Cancer DO Estado de Sao Paulo, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Mateus Trinconi Cunha
- Department of Medical Oncology, ICESP - Instituto do Cancer DO Estado de Sao Paulo, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Giovanna Sawaya Torre
- Department of Radiology, ICESP - Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Raphael L C Araujo
- Digestive Surgery Division, Department of Surgery, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Gilton Marques Fonseca
- Digestive Surgery Division, Department of Gastroenterology, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Andre Tsin Chih Chen
- Radiation Oncology Department - Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Aline Lopes Chagas
- Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Paulo Herman
- Digestive Surgery Division, Department of Gastroenterology, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | | | - Flair Jose Carrilho
- Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
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15
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Du L, Wilson BAP, Li N, Shah R, Dalilian M, Wang D, Smith EA, Wamiru A, Goncharova EI, Zhang P, O’Keefe BR. Discovery and Synthesis of a Naturally Derived Protein Kinase Inhibitor that Selectively Inhibits Distinct Classes of Serine/Threonine Kinases. JOURNAL OF NATURAL PRODUCTS 2023; 86:2283-2293. [PMID: 37843072 PMCID: PMC10616853 DOI: 10.1021/acs.jnatprod.3c00394] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Indexed: 10/17/2023]
Abstract
The DNAJB1-PRKACA oncogenic gene fusion results in an active kinase enzyme, J-PKAcα, that has been identified as an attractive antitumor target for fibrolamellar hepatocellular carcinoma (FLHCC). A high-throughput assay was used to identify inhibitors of J-PKAcα catalytic activity by screening the NCI Program for Natural Product Discovery (NPNPD) prefractionated natural product library. Purification of the active agent from a single fraction of an Aplidium sp. marine tunicate led to the discovery of two unprecedented alkaloids, aplithianines A (1) and B (2). Aplithianine A (1) showed potent inhibition against J-PKAcα with an IC50 of ∼1 μM in the primary screening assay. In kinome screening, 1 inhibited wild-type PKA with an IC50 of 84 nM. Further mechanistic studies including cocrystallization and X-ray diffraction experiments revealed that 1 inhibited PKAcα catalytic activity by competitively binding to the ATP pocket. Human kinome profiling of 1 against a panel of 370 kinases revealed potent inhibition of select serine/threonine kinases in the CLK and PKG families with IC50 values in the range ∼11-90 nM. An efficient, four-step total synthesis of 1 has been accomplished, enabling further evaluation of aplithianines as biologically relevant kinase inhibitors.
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Affiliation(s)
- Lin Du
- Molecular
Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States
| | - Brice A. P. Wilson
- Molecular
Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States
| | - Ning Li
- Center
for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States
| | - Rohan Shah
- Molecular
Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States
| | - Masoumeh Dalilian
- Molecular
Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States
- Leidos
Biomedical Research, Frederick National
Laboratory for Cancer Research, Frederick, Maryland 21702, United States
| | - Dongdong Wang
- Molecular
Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States
| | - Emily A. Smith
- Molecular
Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States
- Leidos
Biomedical Research, Frederick National
Laboratory for Cancer Research, Frederick, Maryland 21702, United States
| | - Antony Wamiru
- Molecular
Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States
- Leidos
Biomedical Research, Frederick National
Laboratory for Cancer Research, Frederick, Maryland 21702, United States
| | - Ekaterina I. Goncharova
- Molecular
Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States
- Leidos
Biomedical Research, Frederick National
Laboratory for Cancer Research, Frederick, Maryland 21702, United States
| | - Ping Zhang
- Center
for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States
| | - Barry R. O’Keefe
- Molecular
Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States
- Natural
Products Branch, Development Therapeutics Program, Division of Cancer
Treatment and Diagnosis, National Cancer
Institute, Frederick, Maryland 21702, United States
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16
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Aloysius MM, Iskander P, Ahmed K, Asija U, Mohammed E, Iskander A, Shah NJ, Goyal H, Khurana V, Simin N, Aswath G, John S. Fibrolamellar hepatocellular carcinoma: An epidemiologic and 5-year cancer survival assessment based off SEER data. Clin Res Hepatol Gastroenterol 2023; 47:102162. [PMID: 37307948 DOI: 10.1016/j.clinre.2023.102162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 06/09/2023] [Indexed: 06/14/2023]
Abstract
The fibrolamellar variant of hepatocellular carcinoma makes up a small percentage of liver tumors. Despite being a subset, it has been noted in the literature to have variations in terms of its epidemiology and intervention recommendations. Using the Surveillance, Epidemiology, and End Results database, 339 cases from 1988 to 2016 were studied. Favorable prognostic epidemiological factors included male sex, younger ages, and white race. Those who underwent any lymph node resection (combined with liver resection) did better than those without lymph node resection; chemotherapy proved beneficial for those where surgery was contraindicated. To our knowledge, this report is the largest conglomerate dataset analyzing prognostic profiles and treatment strategies for fibrolamellar hepatocellular carcinoma.
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Affiliation(s)
- Mark M Aloysius
- The Wright Center for Graduate Medical Education, 501 S Washington Avenue, Scranton, PA, United States
| | - Peter Iskander
- The Wright Center for Graduate Medical Education, 501 S Washington Avenue, Scranton, PA, United States.
| | - Khalid Ahmed
- The Wright Center for Graduate Medical Education, 501 S Washington Avenue, Scranton, PA, United States
| | - Udit Asija
- The Wright Center for Graduate Medical Education, 501 S Washington Avenue, Scranton, PA, United States
| | - Elmkdad Mohammed
- The Wright Center for Graduate Medical Education, 501 S Washington Avenue, Scranton, PA, United States
| | - Anthony Iskander
- Xavier University School of Medicine Aruba, Santa Helenastraat 23, Oranjestad, Aruba
| | - Niraj James Shah
- University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, United States
| | - Hemant Goyal
- The Wright Center for Graduate Medical Education, 501 S Washington Avenue, Scranton, PA, United States
| | - Vikas Khurana
- The Wright Center for Graduate Medical Education, 501 S Washington Avenue, Scranton, PA, United States
| | - Nasr Simin
- The Wright Center for Graduate Medical Education, 501 S Washington Avenue, Scranton, PA, United States
| | - Ganesh Aswath
- Upstate University Hospital, 750 East Adams Street, Syracuse, NY 13210, United States
| | - Savio John
- Upstate University Hospital, 750 East Adams Street, Syracuse, NY 13210, United States
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17
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Gummadi J, Wang X, Xie C. Current Advances in the Treatment of Fibrolamellar Carcinoma of Liver. J Hepatocell Carcinoma 2023; 10:745-752. [PMID: 37215364 PMCID: PMC10198173 DOI: 10.2147/jhc.s406902] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 04/05/2023] [Indexed: 05/24/2023] Open
Abstract
Fibrolamellar carcinoma (FLC) of the liver is a rare type of liver cancer that is prevalent in children and young adults, often less than 40 years old. The etiology is unclear. It presents without underlying liver disease with distinctive histological features such as fibrous collagen bands surrounding the tumor cells. Fusion protein DNAJB1-PRKACA is found in most of the cases. The prognosis of FLC is poor. Even though curative treatment option is surgery for a certain patient population, other treatment modalities including radiation, chemotherapy are currently being used without significant improvement of overall survival. Recently, targeted therapy and immunotherapy have been studied which may provide survival advantage in the future. This review sought to compile data from clinical trials and case reports/series to outline the current state of FLC treatment.
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Affiliation(s)
- Jyotsna Gummadi
- Department of Medicine, MedStar Franklin Square Medical Center, Baltimore, MD, 21237, USA
| | - Xin Wang
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20814, USA
| | - Changqing Xie
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20814, USA
- NCI CCR Liver Cancer Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20814, USA
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18
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Moazzam Z, Alaimo L, Endo Y, Lima HA, Pawlik TM. Predictors, Patterns, and Impact of Adequate Lymphadenectomy in Intrahepatic Cholangiocarcinoma. Ann Surg Oncol 2023; 30:1966-1977. [PMID: 36622527 DOI: 10.1245/s10434-022-13044-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 11/16/2022] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Despite lymph node metastases (LNMs) being associated with worse survival, adequate lymph node evaluation (LNE) has not been universally adopted for intrahepatic cholangiocarcinoma (ICC). We sought to evaluate trends in LNE, predictors of LNE and LNM, as well as the role of adequate lymphadenectomy in stratifying patients relative to survival. METHODS Patients who underwent curative-intent liver resection for ICC (2010-2019) were identified from the National Cancer Database and stratified according to LNE: 0, 1-5 (inadequate lymphadenectomy) and ≥6 (adequate lymphadenectomy). Multivariate logistic regression was utilized to assess predictors of LNE and LNM. Overall survival and receipt of adequate lymphadenectomy were assessed relative to LNM and log-odds of lymph nodes (LODDS). RESULTS Among 6507 patients, adequate lymphadenectomy was performed in only 1118 (17.2%) patients, although compliance with adequate lymphadenectomy increased over time (2010-2012: 14.2% vs. 2016-2019: 18.9%; p < 0.001). After controlling for relevant factors, region (reference: Northeast; Midwest: odds ratio [OR] 1.90, 95% confidence interval [CI] 1.48-2.44; South: OR 1.64, 95% CI 1.28-2.10; West: OR 1.83, 95% CI 1.37-2.44) and preoperative nodal status (reference: cN0; cNx: OR 2.18, 95% CI 1.68-2.95; cN1: OR 3.88, 95% CI 3.02-4.98) strongly predicted adequate lymphadenectomy. Furthermore, adequate lymphadenectomy resulted in higher odds of detecting ≥1 LNMs (OR 2.63, 95% CI 2.25-3.08), regardless of preoperative nodal status. Adequate lymphadenectomy demonstrated an improved ability to stratify patients relative to 5-year survival based on LNM (N0: 51.3% vs. N1: 30.6% vs. N2: 13.7%; p < 0.001) and LODDS (LODDS1: 50.7% vs. LODDS2: 27.4% vs. LODDS3: 15.7%; p < 0.001). CONCLUSIONS Compliance with adequate lymphadenectomy at the time of surgery for ICC remains suboptimal with marked regional variations. Adequate lymphadenectomy was associated with higher odds of detecting LNM and improved survival stratification relative to both LNM and LODDS. Greater emphasis on nodal evaluation is required to ensure optimal management of ICC.
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Affiliation(s)
- Zorays Moazzam
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, Columbus, OH, USA
| | - Laura Alaimo
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, Columbus, OH, USA
| | - Yutaka Endo
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, Columbus, OH, USA
| | - Henrique A Lima
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, Columbus, OH, USA.
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19
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Glavas D, Bao QR, Scarpa M, Ruffolo C, Brown ZJ, Pawlik TM, Spolverato G. Treatment and Prognosis of Fibrolamellar Hepatocellular Carcinoma: a Systematic Review of the Recent Literature and Meta-analysis. J Gastrointest Surg 2023; 27:705-715. [PMID: 36797535 PMCID: PMC10073062 DOI: 10.1007/s11605-023-05621-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 01/24/2023] [Indexed: 02/18/2023]
Abstract
BACKGROUND Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare disease and current efforts are focused on the prognosis and on the development of efficient and specific treatments. This study aimed to review the latest evidence regarding FL-HCC treatment and prognosis. METHODS A systematic review of the literature over the past 10 years regarding FL-HCC, and meta-analysis of 1-, 3-, and 5-year overall survival (OS) comparing FL-HCC and conventional HCC were performed. RESULTS Overall, 1567 articles were screened, of them 21 were selected for the systematic review, and 6 for meta-analysis. Twenty-one studies included a total of 2168 patients with FL-HCC, with a median age ranging from 11 to 56 years. The majority of patients underwent surgical resection or liver transplantation. After a median follow-up ranging from 24 to 58 months, 1-year OS was 67-100% and 5-year OS was 28-65%. A total of 743 patients with FL-HCC and 163,472 with conventional HCC were included in the meta-analysis. There was a significantly improved 1-, 3-, and 5-years OS in the FL-HCC group compared to the conventional HCC group, although high heterogeneity was found. When excluding population-based studies, and including 96 FL-HCC and 221 conventional HCC patients, the heterogeneity was low, and the meta-analysis showed a significantly longer 1-year OS in patients with FL-HCC than conventional HCC; however, there were no differences at 3- and 5-years OS. CONCLUSIONS Surgical resection for FL-HCC is currently the only curative treatment available. FL-HCC is plagued by high-recurrence rates and poor long-term outcomes which may be related to the absence of specific treatment for advanced and recurrent disease.
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Affiliation(s)
- Dajana Glavas
- General Surgery 3, Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), University of Padova, Via Nicolò Giustiniani, 2, PD, 35128, Padova, Italy
| | - Quoc Riccardo Bao
- General Surgery 3, Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), University of Padova, Via Nicolò Giustiniani, 2, PD, 35128, Padova, Italy
| | - Marco Scarpa
- General Surgery 3, Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), University of Padova, Via Nicolò Giustiniani, 2, PD, 35128, Padova, Italy
| | - Cesare Ruffolo
- General Surgery 3, Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), University of Padova, Via Nicolò Giustiniani, 2, PD, 35128, Padova, Italy
| | - Zachary J Brown
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Gaya Spolverato
- General Surgery 3, Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), University of Padova, Via Nicolò Giustiniani, 2, PD, 35128, Padova, Italy.
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20
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Fibrolamellar Hepatocellular Carcinoma: Comprehensive Review of Diagnosis, Imaging, and Management. J Am Coll Surg 2023; 236:399-410. [PMID: 36648268 DOI: 10.1097/xcs.0000000000000476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND Fibrolamellar hepatocellular carcinoma (FLC) is a rare malignancy that primarily affects patients in late adolescence and young adulthood. FLC tumors are characterized by their unique histologic features and a recently discovered genomic alteration, a chimeric fusion protein found in nearly all tumors. This review article provides the latest advancements in diagnosing, imaging, and managing FLC. STUDY DESIGN A comprehensive systematic review was performed using MEDLINE/PubMed and Web of Science databases, with the end of search date being July 1, 2022, regarding FLC diagnosis, imaging, and management. RESULTS Surgical resection remains the mainstay of therapy offering a chance for cure; however, given the incidence of metastatic disease at diagnosis and high rates of distant relapse, systemic therapies remain a crucial component of disease control. Unfortunately, few systemic therapies have demonstrated proven benefits. Consequently, recent efforts have galvanized around single-institute or small consortia-based studies specifically focused on enrolling patients with FLC or using agents with a biologic rationale. CONCLUSIONS FLC has unique demographic, radiologic, and pathologic features. The rarity of these tumors, coupled with the only recent acknowledgment of the genomic abnormality, has likely led to disease underrecognition and deprioritization of collaborative efforts to establish an evidence-based standard of care. Despite R0 resection, most patients experience recurrence. However, surgical resection is feasible for many recurrences and is associated with good survival. The role of chemotherapy is evolving, and further research is required to define its role in managing this disease.
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21
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Chen KY, Popovic A, Hsiehchen D, Baretti M, Griffith P, Bista R, Baghdadi A, Kamel IR, Simon SM, Migler RD, Yarchoan M. Clinical Outcomes in Fibrolamellar Hepatocellular Carcinoma Treated with Immune Checkpoint Inhibitors. Cancers (Basel) 2022; 14:5347. [PMID: 36358766 PMCID: PMC9655068 DOI: 10.3390/cancers14215347] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 10/21/2022] [Accepted: 10/23/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of liver cancer primarily affecting children and young adults. Although considered a subset of hepatocellular carcinoma (HCC), FLC has unique molecular and pathologic characteristics, suggesting that it may require different treatment. Immune checkpoint inhibitors (ICIs) are used in the treatment of HCC, but efficacy and safety in FLC has not been characterized. METHODS We performed a multicenter retrospective analysis of patients with FLC to determine responses to ICI therapy. Response rates were assessed based on RECIST 1.1 criteria, and Kaplan-Meier statistics were used for progression-free survival (PFS) and overall survival (OS). RESULTS FLC tumors were characterized by low tumor mutational burden (TMB) and absent PD-L1 expression. We identified 19 patients who received ICIs, including 15 who received ICI therapy alone [programmed death receptor 1 (PD-1) inhibitor, +/- cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor]. Objective tumor responses were observed in 3/19 patients (15.8%), including 2/15 patients (13.3%) who received ICIs alone, all partial responses. Median PFS and OS were 5.5 and 26.0 months, respectively. Grade 3-4 immune related adverse events were observed in 4/19 (21.1%) patients. CONCLUSIONS ICI therapy has modest clinical activity in FLC, and novel therapeutic combinations are needed.
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Affiliation(s)
- Krista Y. Chen
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Aleksandra Popovic
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - David Hsiehchen
- Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Marina Baretti
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Paige Griffith
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Ranjan Bista
- Department of Pediatrics, Texas Tech University Health Sciences Center, El Paso, TX 79410, USA
| | - Azarakhsh Baghdadi
- Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Ihab R. Kamel
- Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | | | | | - Mark Yarchoan
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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Polychronidis G, Murtha-Lemekhova A, Fuchs J, Karathanasi E, Hoffmann K. A Multidisciplinary Approach to the Management of Fibrolamellar Carcinoma: Current Perspectives and Future Prospects. Onco Targets Ther 2022; 15:1095-1103. [PMID: 36212724 PMCID: PMC9541294 DOI: 10.2147/ott.s296127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/08/2022] [Indexed: 11/23/2022] Open
Abstract
Fibrolamellar carcinoma (FLC) is a rare primary liver tumor affecting predominantly younger and otherwise healthy patients. Typically, FLC presents with advanced disease due to the paucity of typical symptoms and no history of underlying liver disease. Depending on tumor characteristics and the patient's general condition, surgical treatment is the most promising treatment modality. Aggressive resection and liver transplantation have been utilized and are presently indispensable curative treatment options. Under certain circumstances surgical resection is also possible for metachronous metastases or local recurrence. Recent tumor biology discoveries have contributed to improved diagnostic specificity and systemic treatment options.
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Affiliation(s)
- Georgios Polychronidis
- Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Heidelberg, 69120, Germany
| | - Anastasia Murtha-Lemekhova
- Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Heidelberg, 69120, Germany
| | - Juri Fuchs
- Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Heidelberg, 69120, Germany
| | - Evdokia Karathanasi
- Post-Graduate Program “Human Genetics- Genetic Counseling”, Faculty of Medicine, University of Thessaly, Larisa, Greece
| | - Katrin Hoffmann
- Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Heidelberg, 69120, Germany,Correspondence: Katrin Hoffmann, Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, Heidelberg, 69120, Germany, Email
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23
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Na SK. Fibrolamellar hepatocellular carcinoma that was successfully treated with surgical resection: a case report. JOURNAL OF LIVER CANCER 2022; 22:178-182. [PMID: 37383417 PMCID: PMC10035731 DOI: 10.17998/jlc.2022.06.10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 06/03/2022] [Accepted: 06/10/2022] [Indexed: 06/30/2023]
Abstract
Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare malignant hepatic cancer with characteristics that differ from those of typical hepatocellular carcinoma (HCC). Unlike conventional HCC, FLHCC is common in young patients without any underlying liver disease and is known to be associated with a unique gene mutation. This cancer type is rare in Asia, with only a few cases being reported in Korea. We report a case of FLHCC in a young woman that successfully underwent surgical resection. The efficacy of alternative treatments, such as transarterial chemoembolization or systemic chemotherapies, has not yet been established. To conclude, early diagnosis and appropriate surgical resection are important for the treatment of FLHCC.
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Affiliation(s)
- Seong Kyun Na
- Department of Internal Medicine, Jeju National University College of Medicine, Jeju, Korea
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24
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Hu J, Wang Y, Deng L, Yu H, Chen K, Bao W, Chen K, Chen G. Development and validation of a nomogram for predicting the cancer-specific survival of fibrolamellar hepatocellular carcinoma patients. Updates Surg 2022; 74:1589-1599. [PMID: 35713784 DOI: 10.1007/s13304-022-01308-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 05/21/2022] [Indexed: 11/24/2022]
Abstract
Fibrolamellar hepatocellular carcinoma (FLC) is a rare subtype of hepatocellular carcinoma. Our study aimed to construct a nomogram to predict the cancer-specific survival (CSS) of FLC. Data of 200 FLC patients enrolled in the Surveillance, Epidemiology, and End Results (SEER) database were divided into the training group and the validation group. Prognostic factors identified in the univariate and multivariate Cox regression analyses were used to construct the nomogram. The concordance index (C-index), calibration curves, time-dependent receiver operating characteristic curve (ROC), and decision curve analysis (DCA) were used to evaluate the performance of the nomogram. As a result, age ≥ 59, N1 stage, M1 stage, tumor size ≤ 2.0 cm, and no surgery were significantly associated with lower CSS in multivariate Cox regression analysis. The calibration plot showed good consistency of the nomogram between predicted and observed outcomes in the training and validation groups. Compared with the TNM staging system, the prognostic evaluation model (PEM) showed a higher C-index (0.823 vs 0.656). The PEM also showed better predictive performance, with areas under the curve of 0.909 and 0.890 for predicting the 1- and 5-year survival. The AUCs of the TNM stage model for predicting 1- and 5-year survival were 0.629 and 0.787, respectively. In addition, the DCA curve showed that the nomogram had better clinical utility. Finally, we concluded that Age, N stage, M stage, tumor size, and surgery are independent prognostic factors for FLC. PEM established based on these five prognostic indicators can help predict the CSS of patients with FLC.
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Affiliation(s)
- Jiawei Hu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Fuxue Road, Wenzhou, Zhejiang, 325035, People's Republic of China.,Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, People's Republic of China
| | - Yi Wang
- Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, People's Republic of China
| | - Liming Deng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Fuxue Road, Wenzhou, Zhejiang, 325035, People's Republic of China.,Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, People's Republic of China
| | - Haitao Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Fuxue Road, Wenzhou, Zhejiang, 325035, People's Republic of China.,Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, People's Republic of China
| | - Kaiyu Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Fuxue Road, Wenzhou, Zhejiang, 325035, People's Republic of China.,Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, People's Republic of China
| | - Wenming Bao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Fuxue Road, Wenzhou, Zhejiang, 325035, People's Republic of China.,Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, People's Republic of China
| | - Kaiwen Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Fuxue Road, Wenzhou, Zhejiang, 325035, People's Republic of China
| | - Gang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Fuxue Road, Wenzhou, Zhejiang, 325035, People's Republic of China. .,Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, People's Republic of China.
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Abdelhamed W, El-Kassas M. Fibrolamellar hepatocellular carcinoma: A rare but unpleasant event. World J Gastrointest Oncol 2022; 14:1103-1114. [PMID: 35949219 PMCID: PMC9244987 DOI: 10.4251/wjgo.v14.i6.1103] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/19/2022] [Accepted: 05/08/2022] [Indexed: 02/06/2023] Open
Abstract
Fibrolamellar carcinoma (FLC) is a rare variant of hepatocellular carcinoma (HCC), comprising 1%-9% of all HCCs. FLC is a poorly understood malignancy, which seems to be more prevalent in young patients with no underlying liver diseases. The term "fibrolamellar" is derived from thick fibrous collagen bands surrounding the tumor cells. Unlike HCC, cirrhosis and viral hepatitis infection are not predisposing to FLC, and it is not associated with elevations in serum alpha-fetoprotein. FLC patients often present with vague abdominal pain, nausea, malaise, and weight loss. Most cases present are at an advanced stage at the time of initial diagnosis. However, curative treatment options can still be offered to up to 70% of patients. Surgery (resection/liver transplantation) is the mainstay of treatment and the only potentially curative option. FLCs have been less chemo-responsive than the conventional HCC, however, in advanced cases, multimodality treatments can be effective. Recent advances in molecular studies of FLC have found a unique DNAJB1-PRKACA fusion transcript in most of the cases studied. The review aims to describe clinical characteristics, diagnostic methods, and therapeutic modalities for this rare tumor to raise awareness among clinicians and surgeons.
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Affiliation(s)
- Walaa Abdelhamed
- Department of Endemic Medicine, Sohag University, Sohag 14322, Egypt
| | - Mohamed El-Kassas
- Department of Endemic Medicine, Faculty of Medicine, Helwan University, Cairo 11795, Egypt
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26
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Sempokuya T, Forlemu A, Azawi M, Silangcruz K, Khoury N, Ma J, Wong LL. Survival characteristics of fibrolamellar hepatocellular carcinoma: A Surveillance, Epidemiology, and End Results database study. World J Clin Oncol 2022; 13:352-365. [PMID: 35662983 PMCID: PMC9153071 DOI: 10.5306/wjco.v13.i5.352] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 03/29/2022] [Accepted: 04/21/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare and distinct type of hepatocellular carcinoma that frequently presents in an advanced stage in younger patients with no underlying liver disease. Currently, there is a limited understanding of factors that impact outcomes in FL-HCC.
AIM To characterize the survival of FL-HCC by age, race, and surgical intervention.
METHODS This is a retrospective study of The Surveillance, Epidemiology, and End Results database. We identified patients with FL-HCC between 2000-2018 by using an ICD-O-3 site code C22.0 and a histology code 8171/3: Hepatocellular carcinoma, fibrolamellar. In addition, demographics, tumor characteristics, types of surgical procedure, stages, and survival data were obtained. We conducted three separate survival analyses by age groups; ≤ 19, 20-59, and ≥ 60-year-old, and race; White, Black, Hispanic, Asian and Pacific islanders (API), and surgical types; Wedge resection or segmental resection, lobectomy, extended lobectomy (lobectomy + locoregional therapy or resection of the other lobe), and transplant. The Chi-Square test analyzed categorical variables, and continuous variables were examined using the Mann-Whitney U test. The Kaplan-Meier survival curve was used to compare survival. Multivariate analysis was done with Cox regression analysis.
RESULTS We identified 225 FL-HCC patients with a mean age of 36.9. Overall median survival was 34 (95%CI: 27-41) mo. Patients ≤ 19-years-old had more advanced disease with positive lymph nodes status. However, they received more surgical interventions such as a wedge, segmental resection, lobectomy, extended lobectomy, and transplant. Survival for ≤ 19 was 85 (95%CI: 37-137) mo, age 20-59 was 29 (95%CI: 18-41) mo, and age ≥ 60 years was 12 (95%CI: 7-31) mo (P < 0.001). There were no differences in stage, lymph node status, metastasis status, and surgical treatment among races. The median survival were; Whites had 39 (95%CI: 29-63), Blacks 26 (95%CI: 5-92), Hispanics 31 (95%CI: 11-54), and APIs 28 (95%CI: 5-39) mo (P = 0.28). Of 225 patients, 111 FL-HCC patients had surgical procedures. Median survivals for a wedge or segmental resection was 112 (95%CI: 78-NA), lobectomy was 92 (95%CI: 57-NA), extended lobectomy was 54 (95%CI: 23-NA), and a transplant was 63 (95%CI: 20-NA) mo (P < 0.001). The median survival was better in patients who had surgical treatments regardless of lymph nodes or metastasis status (P < 0.001).
CONCLUSION FL-HCC occurs in a primarily younger population, but survival can be prolonged despite the aggressive disease. There were no racial differences in the survival of FL-HCC; however, Asians with FL-HCC tended to be older than in other races. Surgical treatment provided better survival even in those patients with nodal disease or metastases. Although future studies are needed to explore other therapies for FL-HCC, surgical options should be considered in all cases of FL-HCC unless contraindicated.
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Affiliation(s)
- Tomoki Sempokuya
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Arnold Forlemu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Muaataz Azawi
- Division of Gastroenterology and Hepatology, Sanford Center for Digestive Health, Sioux Falls, SD 57105, United States
| | - Krixie Silangcruz
- Department of Medicine, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813, United States
| | - Nathalie Khoury
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Jihyun Ma
- Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Linda L Wong
- Department of Surgery, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813, United States
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Kang S, Magliocca J, Sellers M, Roccaro G, Zheng W, Pectasides M, Draper A, Guadagno J, El-Rayes B, Akce M. Successful liver transplantation of recurrent fibrolamellar carcinoma following clinical and pathologic complete response to triple immunochemotherapy: A case report. Oncol Res Treat 2022; 45:430-437. [PMID: 35537414 DOI: 10.1159/000524872] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 05/01/2022] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Fibrolamellar carcinoma (FLC) is a rare liver cancer that predominantly affects younger patients without a history of liver disease. Surgical resection is the cornerstone of therapy and represents the best potentially curative treatment option. Modest objective responses with cytotoxic chemotherapy alone or combined with immune checkpoint inhibitors (ICIs) have been reported, however there are no established systemic therapy regimens for unresectable or metastatic FLC. CASE PRESENTATION We report a case of a 23-year-old woman with FLC who presented with a 11.5 x 8.3 cm left liver mass and subsequently underwent resection as initial therapy. Molecular analysis of her surgical tissue revealed a DNAJB1-PRKACA fusion gene. The patient developed biopsy-proven recurrent FLC with multiple liver lesions but without any distant metastatic disease only 3 months after initial resection. In light of emerging data, the patient was treated with a novel triple therapy regimen including 5-fluorouracil (5-FU), interferon (IFN) alfa-2b, and nivolumab. Partial radiographic response was achieved after 4 treatments and complete response was achieved after 12 cycles with the combination. The patient received 2 more doses of 5-FU/IFN alfa-2b without nivolumab, and underwent orthotopic liver transplantation (OLT) 6 months after the last dose of ICI. Pathological examination of the explanted liver remarkably confirmed pathologic complete response. She remains recurrence-free and is on active surveillance. DISCUSSION/CONCLUSION For patients with unresectable/recurrent FLC with no distant disease, the combination of 5-FU, IFN alfa-2b, and nivolumab could be an effective systemic therapy option. The use of this chemoimmunotherapy regimen to downstage FLC prior to OLT may be worth investigating further.
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Affiliation(s)
- Sandra Kang
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA,
| | - Joseph Magliocca
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Marty Sellers
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Giorgio Roccaro
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Wei Zheng
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Melina Pectasides
- Department of Radiology and Imaging Services, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Amber Draper
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Jessica Guadagno
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Bassel El-Rayes
- Division of Hematology and Oncology, Department of Internal Medicine, O Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, USA
| | - Mehmet Akce
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
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Dinh TA, Utria AF, Barry KC, Ma R, Abou-Alfa GK, Gordan JD, Jaffee EM, Scott JD, Zucman-Rossi J, O’Neill AF, Furth ME, Sethupathy P. A framework for fibrolamellar carcinoma research and clinical trials. Nat Rev Gastroenterol Hepatol 2022; 19:328-342. [PMID: 35190728 PMCID: PMC9516439 DOI: 10.1038/s41575-022-00580-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/13/2022] [Indexed: 12/17/2022]
Abstract
Fibrolamellar carcinoma (FLC), a rare, lethal hepatic cancer, occurs primarily in adolescents and young adults. Unlike hepatocellular carcinoma, FLC has no known association with viral, metabolic or chemical agents that cause cirrhosis. Currently, surgical resection is the only treatment demonstrated to achieve cure, and no standard of care exists for systemic therapy. Progress in FLC research illuminates a transition from an obscure cancer to one for which an interactive community seems poised to uncover fundamental mechanisms and initiate translation towards novel therapies. In this Roadmap, we review advances since the seminal discovery in 2014 that nearly all FLC tumours express a signature oncogene (DNAJB1-PRKACA) encoding a fusion protein (DNAJ-PKAc) in which the J-domain of a heat shock protein 40 (HSP40) co-chaperone replaces an amino-terminal segment of the catalytic subunit of the cyclic AMP-dependent protein kinase (PKA). Important gains include increased understanding of oncogenic pathways driven by DNAJ-PKAc; identification of potential therapeutic targets; development of research models; elucidation of immune mechanisms with potential for the development of immunotherapies; and completion of the first multicentre clinical trials of targeted therapy for FLC. In each of these key areas we propose a Roadmap for future progress.
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Affiliation(s)
- Timothy A. Dinh
- Medical Scientist Training Program, University of North Carolina, Chapel Hill, NC, USA.,Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA.,These authors contributed equally: Timothy A. Dinh, Alan F. Utria, Kevin C. Barry
| | - Alan F. Utria
- Department of Surgery, University of Washington, Seattle, WA, USA.,These authors contributed equally: Timothy A. Dinh, Alan F. Utria, Kevin C. Barry
| | - Kevin C. Barry
- Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,These authors contributed equally: Timothy A. Dinh, Alan F. Utria, Kevin C. Barry
| | - Rosanna Ma
- Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA
| | - Ghassan K. Abou-Alfa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA
| | - John D. Gordan
- Gastrointestinal oncology, University of California at San Francisco Comprehensive Cancer Center, San Francisco, CA, USA
| | - Elizabeth M. Jaffee
- Department of oncology, Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - John D. Scott
- Department of Pharmacology, University of Washington, Seattle, WA, USA
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne université, Inserm, Université de Paris, Functional Genomics of Solid Tumors, Paris, France
| | - Allison F. O’Neill
- Department of Paediatric Hematology/oncology, Dana-Farber Cancer Institute, Harvard University, Boston, MA, USA
| | - Mark E. Furth
- Fibrolamellar Cancer Foundation, Greenwich, CT, USA.,;
| | - Praveen Sethupathy
- Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA.,;
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Milano AF. Cancer of the Liver, Intrahepatic Bile Ducts, Gallbladder, Exocrine and Neuroendocrine Pancreas: 20-Year Comparative Survival and Mortality Analysis by Age, Sex, Race, Stage, Grade, Cohort Entry Time-Period, Disease Duration & Selected ICD-O-3 Oncologic Phenotypes: A Systematic Review of 367,420 Cases for Diagnosis Years 1973-2014: (SEER*Stat 8.3.4). J Insur Med 2022; 49:60-96. [PMID: 35051267 DOI: 10.17849/insm-49-2-1-36.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 02/20/2019] [Indexed: 11/20/2022]
Abstract
This article summarizes the results of a review of adult invasive primary cancers of the liver, intrahepatic bile ducts, gallbladder, exocrine and endocrine pancreas, as recorded in the SEER Program of the National Cancer Institute for diagnosis years 1973-2014 (SEER Stat 8.3.4).
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Polychronidis G, Feng J, Murtha-Lemekhova A, Heger U, Mehrabi A, Hoffmann K. Factors Influencing Overall Survival for Patients with Fibrolamellar Hepatocellular Carcinoma: Analysis of the Surveillance, Epidemiology, and End Results Database. Int J Gen Med 2022; 15:393-406. [PMID: 35035232 PMCID: PMC8754463 DOI: 10.2147/ijgm.s338066] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/03/2021] [Indexed: 12/19/2022] Open
Abstract
Background The study aimed to develop a nomogram to predict overall survival (OS) for patients with FLC using a national database. Methods The Surveillance, Epidemiology, and End Results database of the National Cancer Institute was reviewed to identify FLC cases with histological confirmation between 2004 and 2014. Cox proportional hazards models were used to identify factors associated with OS. The validation of the nomogram was performed using concordance index (C-index) and calibration curves. Results Out of 170 cases with complete follow-up, 87 received surgery/ablation and 12 received transplantation with significantly higher OS than chemotherapy alone while transplantation combined with chemotherapy showed better survival than solely transplantation. The combination of surgery and chemotherapy showed worse OS than surgery alone. Survival was negatively influenced by T4 stadium (HR = 5.91), while young age and surgery were positive predictive factors. There was no influence of gender, ethnicity or nodal status on survival. The rate of AFP positivity was comparable with and without the presence of distal metastases. Conclusion FLC survival is greatly dependent upon appropriate surgical management irrespective of tumor stadium.
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Affiliation(s)
- Georgios Polychronidis
- Department of General, Visceral and Transplant Surgery, Heidelberg University Clinic, Heidelberg, Germany
| | - Jincheng Feng
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Anastasia Murtha-Lemekhova
- Department of General, Visceral and Transplant Surgery, Heidelberg University Clinic, Heidelberg, Germany
| | - Ulrike Heger
- Department of General, Visceral and Transplant Surgery, Heidelberg University Clinic, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplant Surgery, Heidelberg University Clinic, Heidelberg, Germany
| | - Katrin Hoffmann
- Department of General, Visceral and Transplant Surgery, Heidelberg University Clinic, Heidelberg, Germany
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Rela M, Rammohan A, Reddy MS. Liver Tumors in Children. TEXTBOOK OF PEDIATRIC GASTROENTEROLOGY, HEPATOLOGY AND NUTRITION 2022:983-994. [DOI: 10.1007/978-3-030-80068-0_72] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Lang SA, Bednarsch J, Czigany Z, Joechle K, Kroh A, Amygdalos I, Strnad P, Bruns T, Heise D, Ulmer F, Neumann UP. Liver transplantation in malignant disease. World J Clin Oncol 2021; 12:623-645. [PMID: 34513597 PMCID: PMC8394155 DOI: 10.5306/wjco.v12.i8.623] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 06/15/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation for malignant disease has gained increasing attention as part of transplant oncology. Following the implementation of the Milan criteria, hepatocellular carcinoma (HCC) was the first generally accepted indication for transplantation in patients with cancer. Subsequently, more liberal criteria for HCC have been developed, and research on this topic is still ongoing. The evident success of liver transplantation for HCC has led to the attempt to extend its indication to other malignancies. Regarding perihilar cholangiocarcinoma, more and more evidence supports the use of liver transplantation, especially after neoadjuvant therapy. In addition, some data also show a benefit for selected patients with very early stage intrahepatic cholangiocarcinoma. Hepatic epithelioid hemangioendothelioma is a very rare but nonetheless established indication for liver transplantation in primary liver cancer. In contrast, patients with hepatic angiosarcoma are currently not considered to be optimal candidates. In secondary liver tumors, neuroendocrine cancer liver metastases are an accepted but comparability rare indication for liver transplantation. Recently, some evidence has been published supporting the use of liver transplantation even for colorectal liver metastases. This review summarizes the current evidence for liver transplantation for primary and secondary liver cancer.
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Affiliation(s)
- Sven Arke Lang
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Katharina Joechle
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Andreas Kroh
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Iakovos Amygdalos
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Pavel Strnad
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Tony Bruns
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Daniel Heise
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Florian Ulmer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
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Rare variants of primary liver cancer: Fibrolamellar, combined, and sarcomatoid hepatocellular carcinomas. Eur J Med Genet 2021; 64:104313. [PMID: 34418585 DOI: 10.1016/j.ejmg.2021.104313] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 06/21/2021] [Accepted: 07/22/2021] [Indexed: 01/07/2023]
Abstract
Hepatocellular carcinoma (HCC) constitutes 80% of all primary liver cancers. Based on key developments in the understanding of its carcinogenesis and the advancement of treatment options, detailed algorithms and practice guidelines have been published to guide the clinical management of HCC. Furthermore, several subclasses of HCC have been described based on molecular profiles and linked to pathological characteristics, clinical features, and disease aggressiveness. Most recently, the combination of the checkpoint inhibitor atezolizumab plus bevacizumab has significantly increased treatment response in the first line systemic treatment of HCC. Unfortunately, rare HCC variants, in particular fibrolamellar liver cancer (FLC), combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CCA), and sarcomatoid hepatocellular carcinoma (sHCC), were excluded from phase III studies. Therefore, data for decision-making and treatment allocation for these distinct entities, representing 1-5% of all primary liver cancers, is scarce. Moreover, most of the knowledge available for these rare HCC variants is based on registry data and retrospective studies. In this position paper, we briefly summarize the current clinical knowledge regarding FLC, cHCC-CCA, and sHCC. Based on our summary, we propose future clinical research activities within the framework of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER).
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Abstract
PURPOSE Pediatric hepatocellular carcinoma is rarely seen in childhood. It constitutes approximately 1% of childhood solid organ malignancies. Pediatric hepatocellular carcinoma is the second most common malignant liver tumor after hepatoblastoma in children. In this review, we aimed to review the diagnosis and treatment of pediatric hepatocellular carcinoma in the light of the latest literature. METHODS We reviewed the literature in terms of the diagnosis and treatment of pediatric hepatocellular carcinoma. RESULTS Hepatocellular carcinoma (HCC) and hepatoblastoma constitute 0.5-1.5% of all childhood malignant tumors. HCC is responsible for 27% of all liver tumors and 4% of all pediatric liver transplantations. While 99.6% of HCC is seen in adults, only 0.4% of it is seen in pediatric patients. Etiological predisposition and biological behavior are different from adults. In a child with cirrhosis or liver disease, HCC should be suspected in the presence of a high level of AFP and an abnormal nodule on ultrasonography. Hepatoblastoma should be considered first in the differential diagnosis. CONCLUSION Treatment of pediatric HCC is challenging. Complete surgical resection is essential for the cure. To this end, different neoadjuvant chemotherapy protocols have been designed to convert non-resectable tumors into resectable tumors. For tumors that cannot be resected, liver transplantation for each patient with childhood HCC should be decided individually.
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Affiliation(s)
- Fatma İlknur Varol
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Faculty of Medicine, Inonu University, 244280, Malatya, Turkey.
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35
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Luo J, Zheng J, Hao W, Zeng H, Zhang Z, Shao G. lncRNA PCAT6 facilitates cell proliferation and invasion via regulating the miR-326/hnRNPA2B1 axis in liver cancer. Oncol Lett 2021; 21:471. [PMID: 33907581 PMCID: PMC8063269 DOI: 10.3892/ol.2021.12732] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 02/26/2021] [Indexed: 12/11/2022] Open
Abstract
Liver cancer is one of the most common malignant human tumors with the highest morbidity and mortality rates of all cancer types in China. Evidence suggests that long non-coding RNA prostate cancer-associated transcript 6 (PCAT6) plays an essential role in tumor progression. However, the roles and mechanism of PCAT6 in liver cancer remain unclear. The present study showed that the expression of PCAT6 and heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) was upregulated in liver cancer tissues compared with non-cancerous tissues and were associated with poor overall survival time, whereas microRNA (miR)-326 expression was downregulated. Moreover, knockdown of PCAT6 significantly inhibited the proliferation and invasion of liver cancer cells in vitro and in vivo. A dual-luciferase reporter gene assay demonstrated that PCAT6 could bind to miR-326 and that hnRNPA2B1 was a direct target gene of miR-326. Mechanistically, silenced PCAT6 suppressed the malignant phenotype of liver cancer cells through upregulating the inhibitory effect of miR-326 on hnRNPA2B1 expression. Taken together, these data demonstrated that knockdown of PCAT6 inhibited liver cancer progression through regulation of the miR-326/hnRNPA2B1 axis, suggesting that PCAT6 functions as an oncogene and may be a useful biomarker for the future diagnosis and treatment of liver cancer.
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Affiliation(s)
- Jun Luo
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310022, P.R. China
| | - Jiaping Zheng
- Department of Intervention, The Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
| | - Weiyuan Hao
- Department of Intervention, The Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
| | - Hui Zeng
- Department of Intervention, The Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
| | - Zhewei Zhang
- Department of Intervention, The Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
| | - Guoliang Shao
- Department of Intervention, The Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
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Fu T, Ding H, Xu C, Zhu Y, Xue L, Lin F. Imaging findings of fibrolamellar hepatocellular carcinomas on ultrasonography: A comparison with conventional hepatocellular carcinomas. Clin Hemorheol Microcirc 2021; 77:49-60. [PMID: 32924993 DOI: 10.3233/ch-200896] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Fibrolamellar hepatocellular carcinoma (FLHCC) is an unusual variant of hepatocellular carcinoma (HCC). Revealing the imaging features is important to the diagnosis of FLHCC. OBJECTIVE The aim of this study was to investigate the imaging characteristics of FLHCCs. METHODS This retrospective study included 29 patients with histopathologically proved FLHCC and 96 patients proved HCC. All patients underwent an ultrasound examination pre-operation. RESULTS The average maximum diameters of the FLHCC and HCC lesions were 7.4±4.1 cm and 4.1±3.0 cm, respectively. On the ultrasound, 79.3% of the FLHCCs and 12.3% of the HCCs showed the internal hyperechoic area; 48.3% of the FLHCCs and 3.3% of the HCCs displayed a strip-like attenuation. Calcification was noted in 20.7% of the FLHCCs, while none in HCCs. On the contrast-enhanced ultrasound (CEUS), all FLHCC lesions and 87.7% of the HCCs displayed hyperenhancement in the arterial phase. An internal, unenhanced central scar appeared in all FLHCCs, while none in HCCs. CONCLUSIONS The ultrasonographic features of FLHCC lesions indicate that they are relatively large masses showing the internal hyperechoic area or strip-like attenuation or calcification on the US and hypervascularity with an unenhanced central scar on the CEUS as compared with conventional HCC lesions.
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Affiliation(s)
- Tiantian Fu
- Department of Ultrasound, Shanghai Institute of Medical Imaging, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hong Ding
- Department of Ultrasound, Huashan Hospital, Fudan University, Shanghai, China
| | - Chen Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuli Zhu
- Department of Ultrasound, Shanghai Institute of Medical Imaging, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Liyun Xue
- Department of Ultrasound, Shanghai Institute of Medical Imaging, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Feng Lin
- School of Computer Science and Engineering, Nanyang Technological University, Singapore, Singapore
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Al Zahrani A, Alfakeeh A. Fibrolamellar hepatocellular carcinoma treated with atezolizumab and bevacizumab: two case reports. J Med Case Rep 2021; 15:132. [PMID: 33722275 PMCID: PMC7962306 DOI: 10.1186/s13256-021-02695-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 01/26/2021] [Indexed: 02/07/2023] Open
Abstract
Background Fibrolamellar hepatocellular carcinoma is a unique tumor of the liver that differs from the classical hepatocellular carcinoma in diagnosis, behavior, and possibly treatment. There is usually absent underlying liver disease, and it usually occurs in young patients. The survival outcomes in localized fibrolamellar hepatocellular carcinoma are perhaps better than in classical hepatocellular carcinoma if treated early and radically. On the other hand, the prognosis remains poor for locally advanced and metastatic fibrolamellar hepatocellular carcinoma. Many reports suggested a limited benefit from systemic chemotherapy. Sorafenib also did not show major effects on fibrolamellar hepatocellular carcinoma. Given the rarity of fibrolamellar hepatocellular carcinoma, lack of large studies, and absence of standard treatment, the treatment decisions rely on case reports, previously reported cases series, and expert opinions. Recent studies have shown promising effects of immunotherapy with checkpoint inhibitors in the first- and second-line therapy of hepatocellular carcinoma. Atezolizumab with bevacizumab regimen has been approved recently as a first-line treatment for classical hepatocellular carcinoma. Currently, there are no reports yet on the use of atezolizumab with bevacizumab for fibrolamellar hepatocellular carcinoma. Case report In this article, we present two Arabic patients with advanced fibrolamellar hepatocellular carcinoma who received atezolizumab and bevacizumab combinations but did not show any clinical benefits. Conclusion While atezolizumab and bevacizumab combinations had shown benefits in classical hepatocellular carcinoma, the current data showed a lack of benefit and tumor response in fibrolamellar hepatocellular carcinoma.
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Affiliation(s)
- Ali Al Zahrani
- Department of Medical Oncology, Comprehensive Cancer Center, King Fahad Medical City, Makkah Al Mukarramah Branch Road, Riyadh, 12231, Kingdom of Saudi Arabia.
| | - Ali Alfakeeh
- Department of Medical Oncology, Comprehensive Cancer Center, King Fahad Medical City, Makkah Al Mukarramah Branch Road, Riyadh, 12231, Kingdom of Saudi Arabia
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Olivieri C, Walker C, Karamafrooz A, Wang Y, Manu VS, Porcelli F, Blumenthal DK, Thomas DD, Bernlohr DA, Simon SM, Taylor SS, Veglia G. Defective internal allosteric network imparts dysfunctional ATP/substrate-binding cooperativity in oncogenic chimera of protein kinase A. Commun Biol 2021; 4:321. [PMID: 33692454 PMCID: PMC7946884 DOI: 10.1038/s42003-021-01819-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 01/29/2021] [Indexed: 02/08/2023] Open
Abstract
An aberrant fusion of the DNAJB1 and PRKACA genes generates a chimeric protein kinase (PKA-CDNAJB1) in which the J-domain of the heat shock protein 40 is fused to the catalytic α subunit of cAMP-dependent protein kinase A (PKA-C). Deceivingly, this chimeric construct appears to be fully functional, as it phosphorylates canonical substrates, forms holoenzymes, responds to cAMP activation, and recognizes the endogenous inhibitor PKI. Nonetheless, PKA-CDNAJB1 has been recognized as the primary driver of fibrolamellar hepatocellular carcinoma and is implicated in other neoplasms for which the molecular mechanisms remain elusive. Here we determined the chimera's allosteric response to nucleotide and pseudo-substrate binding. We found that the fusion of the dynamic J-domain to PKA-C disrupts the internal allosteric network, causing dramatic attenuation of the nucleotide/PKI binding cooperativity. Our findings suggest that the reduced allosteric cooperativity exhibited by PKA-CDNAJB1 alters specific recognitions and interactions between substrates and regulatory partners contributing to dysregulation.
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Affiliation(s)
- Cristina Olivieri
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Caitlin Walker
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Adak Karamafrooz
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Yingjie Wang
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
- Chemistry, University of Minnesota, Minneapolis, MN, USA
- Shenzhen Bay Laboratory, Shenzhen, China
| | - V S Manu
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Fernando Porcelli
- DIBAF - University of Tuscia - Largo dell' Università, Viterbo, Italy
| | - Donald K Blumenthal
- Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA
| | - David D Thomas
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - David A Bernlohr
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Sanford M Simon
- Laboratory of Cellular Biophysics, Rockefeller University, New York, NY, USA
| | - Susan S Taylor
- Department of Chemistry and Biochemistry and Pharmacology, University of California at San Diego, La Jolla, CA, USA
| | - Gianluigi Veglia
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA.
- Chemistry, University of Minnesota, Minneapolis, MN, USA.
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Gottlieb S, O'Grady C, Gliksberg A, Kent P. Early Experiences with Triple Immunochemotherapy in Adolescents and Young Adults with High-Risk Fibrolamellar Carcinoma. Oncology 2021; 99:310-317. [PMID: 33690232 DOI: 10.1159/000513358] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 10/21/2020] [Indexed: 11/19/2022]
Abstract
INTRODUCTION There are no standard systemic therapies for the treatment of fibrolamellar carcinoma (FLC), as surgery remains the only definitive option. We share our experiences using systemic "triple therapy" (TT) with 5-fluorouracil, interferon, and nivolumab for the treatment of relapsed, refractory, metastatic, or unresectable FLC. METHODS Data from all patients who received TT from May 2018 to July 2020 were reviewed to assess response, survival, and toxicity. RESULTS A total of 22 patients were treated with TT, of which 14 (median age of 21 years) were evaluable. They received a median of 18 cycles (8-44). At the time of analysis, the median progression-free survival was 9 months (4.5-26), 29% longer than prior to TT, with 5 patients achieving clinical remission, 8 patients stable or improving, and 1 progression. Overall objective response (clinical remission + partial response) was 50% and tumor control rate (clinical remission + partial response + stable disease) was 93%. Two patients withdrew from treatment due to side effects. DISCUSSION/CONCLUSION Our early results support TT as a promising medical option to slow disease progression and prolong survival in high-risk patients with FLC. TT can be administered in the outpatient setting and has shown good tolerability. Further longitudinal data is needed to confirm outcomes, especially in patients still early in their treatment.
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Affiliation(s)
- Sara Gottlieb
- Rush University Medical Center, Chicago, Illinois, USA
| | | | - Ariel Gliksberg
- Department of Pediatrics, Division of Hematology and Oncology, Rush University Medical Center, Chicago, Illinois, USA
| | - Paul Kent
- Department of Pediatrics, Division of Hematology and Oncology, Rush University Medical Center, Chicago, Illinois, USA,
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Bacinschi X, Zgura AF, Mercan-Stanciu A, Grasu M, Herlea V, Toma L, Dodot M, Martiniuc A, Anghel R, Haineala B. Management of Diagnosis and Treatment in a Case of Fibrolamellar Carcinoma. CANCER DIAGNOSIS & PROGNOSIS 2021; 1:23-28. [PMID: 35399695 PMCID: PMC8962773 DOI: 10.21873/cdp.10004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 03/05/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND/AIM Fibrolamellar carcinoma is a rare primary hepatic malignancy that has recently been recognized as a distinct clinical entity, highly different from the well-known hepatocellular carcinoma. This report describes the clinical and paraclinical aspects of the fibrolamellar carcinoma, emphasizing its particularities. CASE REPORT A 30-year-old patient presented to the hospital with nonspecific symptoms and weight loss, with imaging findings showing abdominal and mediastinal masses. Multiple biopsies were performed, leading to a diagnosis of metastatic fibrolamellar carcinoma. Given the extent of the disease, systemic drug treatment was administered, although prognosis was poor with tumor growth, resulting in biliary duct invasion. CONCLUSION Fibrolamellar carcinoma is a rare type of malignancy, with a difficult differential diagnosis in which imaging techniques are important but for which biopsy remains the gold standard. The prognosis depends on tumor extent and may include surgical methods or chemotherapy.
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Affiliation(s)
- Xenia Bacinschi
- Department of Oncology-Radiotherapy, Prof. Dr. Alexandru Trestioreanu Institute of Oncology,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Anca Florina Zgura
- Department of Oncology-Radiotherapy, Prof. Dr. Alexandru Trestioreanu Institute of Oncology,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Adriana Mercan-Stanciu
- Department of Internal Medicine II, Fundeni Clinical Institute,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Mugur Grasu
- Department of Interventional Radiology, Fundeni Clinical Institute,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Vlad Herlea
- Department of Pathology, Fundeni Clinical Institute, Bucharest, Romania
| | - Letitia Toma
- Department of Internal Medicine II, Fundeni Clinical Institute,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Mihai Dodot
- Department of Internal Medicine II, Fundeni Clinical Institute,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Alexandru Martiniuc
- Department of General Surgery, Fundeni Clinical Institute,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Rodica Anghel
- Department of Oncology-Radiotherapy, Prof. Dr. Alexandru Trestioreanu Institute of Oncology,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Bogdan Haineala
- Department of Internal Medicine II, Fundeni Clinical Institute,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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Gigante E, Paradis V, Ronot M, Cauchy F, Soubrane O, Ganne-Carrié N, Nault JC. New insights into the pathophysiology and clinical care of rare primary liver cancers. JHEP Rep 2021; 3:100174. [PMID: 33205035 PMCID: PMC7653076 DOI: 10.1016/j.jhepr.2020.100174] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 08/06/2020] [Accepted: 08/10/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocholangiocarcinoma, fibrolamellar carcinoma, hepatic haemangioendothelioma and hepatic angiosarcoma represent less than 5% of primary liver cancers. Fibrolamellar carcinoma and hepatic haemangioendothelioma are driven by unique somatic genetic alterations (DNAJB1-PRKCA and CAMTA1-WWTR1 fusions, respectively), while the pathogenesis of hepatocholangiocarcinoma remains more complex, as suggested by its histological diversity. Histology is the gold standard for diagnosis, which remains challenging even in an expert centre because of the low incidences of these liver cancers. Resection, when feasible, is the cornerstone of treatment, together with liver transplantation for hepatic haemangioendothelioma. The role of locoregional therapies and systemic treatments remains poorly studied. In this review, we aim to describe the recent advances in terms of diagnosis and clinical management of these rare primary liver cancers.
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Key Words
- 5-FU, 5-Fluorouracil
- AFP, alpha-fetoprotein
- APHE, arterial phase hyperenhancement
- CA19-9, carbohydrate antigen 19-9
- CCA, cholangiocarcinoma
- CEUS, contrast-enhanced ultrasound
- CK, cytokeratin
- CLC, cholangiolocellular carcinoma
- EpCAM, epithelial cell adhesion molecule
- FISH, fluorescence in situ hybridisation
- FLC, fibrolamellar carcinoma
- Fibrolamellar carcinoma
- HAS, hepatic angiosarcoma
- HCC, hepatocellular carcinoma
- HEH, hepatic epithelioid haemangioendothelioma
- HepPar1, hepatocyte specific antigen antibody
- Hepatic angiosarcoma
- Hepatic hemangioendothelioma
- Hepatocellular carcinoma
- Hepatocholangiocarcinoma
- IHC, immunohistochemistry
- LI-RADS, liver imaging reporting and data system
- LT, liver transplantation
- Mixed tumor
- RT-PCR, reverse transcription PCR
- SIRT, selective internal radiation therapy
- TACE, transarterial chemoembolisation
- WHO, World Health Organization
- cHCC-CCA, combined hepatocholangiocarcinoma
- iCCA, intrahepatic cholangiocarcinoma
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Affiliation(s)
- Elia Gigante
- Service d’hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bobigny, France
- Centre de recherche sur l’inflammation, Inserm, Université de Paris, INSERM UMR 1149 « De l'inflammation au cancer », Paris, France
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Paris, France
| | - Valérie Paradis
- Centre de recherche sur l’inflammation, Inserm, Université de Paris, INSERM UMR 1149 « De l'inflammation au cancer », Paris, France
- Service d'anatomie pathologique, Hôpitaux Universitaires Paris-Nord-Val-de-Seine, Assistance-Publique Hôpitaux de Paris, Clichy, France
- Université de Paris, Paris, France
| | - Maxime Ronot
- Centre de recherche sur l’inflammation, Inserm, Université de Paris, INSERM UMR 1149 « De l'inflammation au cancer », Paris, France
- Service de radiologie, Hôpital Beaujon, Hôpitaux Universitaires Paris-Nord-Val-de-Seine, Assistance-Publique Hôpitaux de Paris, Clichy, France
- Université de Paris, Paris, France
| | - François Cauchy
- Centre de recherche sur l’inflammation, Inserm, Université de Paris, INSERM UMR 1149 « De l'inflammation au cancer », Paris, France
- Service de chirurgie hépato-bilio-pancréatique et transplantation hépatique, Hôpitaux Universitaires Paris-Nord-Val-de-Seine, Assistance-Publique Hôpitaux de Paris, Clichy, France
- Université de Paris, Paris, France
| | - Olivier Soubrane
- Centre de recherche sur l’inflammation, Inserm, Université de Paris, INSERM UMR 1149 « De l'inflammation au cancer », Paris, France
- Service de chirurgie hépato-bilio-pancréatique et transplantation hépatique, Hôpitaux Universitaires Paris-Nord-Val-de-Seine, Assistance-Publique Hôpitaux de Paris, Clichy, France
- Université de Paris, Paris, France
| | - Nathalie Ganne-Carrié
- Service d’hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bobigny, France
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Paris, France
- Centre de Recherche des Cordeliers, Inserm, Sorbonne Université, Université Paris, INSERM UMR 1138, Functional Genomics of Solid Tumors, F-75006, Paris, France
| | - Jean-Charles Nault
- Service d’hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bobigny, France
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Paris, France
- Centre de Recherche des Cordeliers, Inserm, Sorbonne Université, Université Paris, INSERM UMR 1138, Functional Genomics of Solid Tumors, F-75006, Paris, France
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Abstract
Hepatocellular carcinoma (HCC) is a lethal malignancy with poor prognosis. More than 80% of patients are diagnosed at an advanced stage, and most patients with HCC also have liver cirrhosis that complicates cancer management. No targeted treatment options currently exist outside genomics-based clinical trials. Multiple tyrosine kinase inhibitors (mTKIs) such as sorafenib, lenvatinib, cabozantinib, and regorafenib have been used to treat advanced hepatocellular carcinoma (aHCC). Immune checkpoint inhibitors including nivolumab and pembrolizumab have shown survival benefit. More recently, atezolizumab in combination with bevacizumab resulted in improved overall survival and progression-free survival, compared with sorafenib in patients with aHCC in the first-line setting. The combination of nivolumab with ipilimumab as an alternative in the treatment of patients treated with sorafenib has inspired various combination studies of immune checkpoint inhibitors. Currently, ongoing studies of systemic therapy consist of various immune-based combination therapies. Finally, there is no established adjuvant and neoadjuvant therapy although a few early phase studies show promising results. In this chapter, we summarize current approaches of systemic treatment in patients with liver cancer.
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Affiliation(s)
- Tarik Demir
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
| | - Sunyoung S Lee
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
| | - Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
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Ljuboja D, Weinstein JL, Ahmed M, Sarwar A. Extrahepatic transarterial radioembolization to treat fibrolamellar hepatocellular carcinoma: A case report. Radiol Case Rep 2020; 15:2613-2616. [PMID: 33088374 PMCID: PMC7566208 DOI: 10.1016/j.radcr.2020.09.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 09/12/2020] [Accepted: 09/12/2020] [Indexed: 11/26/2022] Open
Abstract
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare primary liver tumor that typically presents at an advanced stage in early adolescents and adults with no underlying liver disease. Surgical resection is the first-line treatment, and patients who are not surgical candidates face limited treatment options with poor long-term outcomes. Herein we report the first documented, technically successful treatment of FL-HCC with extrahepatic spread using transarterial radioembolization (TARE) in a 16-year-old male patient with surgically unresectable disease. Subsequent imaging revealed tumor necrosis and a 20% reduction in size, and the patient survived 20 months post-treatment, a marked improvement relative to historical data in the literature. Further research should examine the potential role of yttrium-90 TARE in the treatment of FL-HCC patients with metastatic disease.
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Affiliation(s)
- Damir Ljuboja
- Harvard Medical School, 25 Shattuck St, Boston, MA 02115, USA.,Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA
| | - Jeffrey L Weinstein
- Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA
| | - Muneeb Ahmed
- Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA
| | - Ammar Sarwar
- Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA
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Anysz-Grodzicka A, Podgorska J, Cieszanowski A. State-of-the-art MR Imaging of Uncommon Hepatocellular Tumours: Fibrolamellar Hepatocellular Carcinoma and Combined Hepatocellularcholangiocarcinoma. Curr Med Imaging 2020; 15:269-280. [PMID: 31989878 DOI: 10.2174/1573405614666180927113622] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 09/12/2018] [Accepted: 09/14/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Fibrolamellar Carcinoma (FLC) and Combined Hepatocellular- Cholangiocarcinoma (CHC) are rare primary liver tumours, which are related to different clinical settings. In both tumours, correlation with clinical data and laboratory tests are extremely important. DISCUSSION Typically, FLC is diagnosed in young patients without any chronic disease and with normal biochemical tests, whereas CHC arises in cirrhotic patients with elevated tumour markers: AFP and/or CA 19-9. The review describes epidemiology, aetiology, pathogenesis, radiological features and treatment of these tumours. Imaging features typical for FLC are: The presence of central scar, calcifications, the large size, heterogeneous and early contrast-enhancement. CONCLUSION The diagnosis of CHC may be suggested in case of elevation of both AFP and CA 19- 9 or inconsistency between elevated tumour markers and imaging findings (i.e., elevated CA 19-9 and radiological features of HCC, or elevated AFP with imaging findings characteristic of ICC).
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Affiliation(s)
- Agnieszka Anysz-Grodzicka
- Department of Radiology, Maria Sklodowska-Curie Memorial Cancer Centre, Institute of Oncology, Warsaw, Poland
| | - Joanna Podgorska
- Department of Clinical Radiology, Medical University of Warsaw, Warsaw, Poland
| | - Andrzej Cieszanowski
- Department of Radiology, Maria Sklodowska-Curie Memorial Cancer Centre, Institute of Oncology, Warsaw, Poland
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Lemekhova A, Hornuss D, Polychronidis G, Mayer P, Rupp C, Longerich T, Weiss KH, Büchler M, Mehrabi A, Hoffmann K. Clinical features and surgical outcomes of fibrolamellar hepatocellular carcinoma: retrospective analysis of a single-center experience. World J Surg Oncol 2020; 18:93. [PMID: 32397993 PMCID: PMC7218513 DOI: 10.1186/s12957-020-01855-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 04/16/2020] [Indexed: 02/06/2023] Open
Abstract
Background Clinicopathological features and surgical outcomes of patients with fibrolamellar hepatocellular carcinoma (FL-HCC) are underreported. The aim of this study is to describe clinical characteristics and surgical outcomes for patients with this rare tumor to raise awareness among clinicians and surgeons. Methods Retrospective review of records of a tertiary referral center and specialized liver unit was performed. Out of 3623 patients who underwent liver resection, 366 patients received surgical treatment for HCC; of them, eight (2.2%) had FL-HCC and were resected between October 2001 and December 2018. Results Eight patients (3 males and 5 females) with FL-HCC (median age 26 years) underwent primary surgical treatment. All patients presented with unspecific symptoms or were diagnosed as incidental finding. No patient had cirrhosis or other underlying liver diseases. Coincidentally, three patients (37.5%) had a thromboembolic event prior to admission. The majority of patients had BCLC stage C and UICC stage IIIB/IVA; four patients (50%) presented with lymph node metastases. The median follow-up period was 33.5 months. The 1-year survival was 71.4%, and 3-year survival was 57.1%. Median survival was at 36.4 months. Five patients (62.5%) developed recurrent disease after a median disease-free survival of 9 months. Two patients (25.0%) received re-resection. Conclusion FL-HCC is a rare differential diagnosis of liver masses in young patients. Since the prognosis is limited, patients with incidental liver tumors or lesions with suspicious features in an otherwise healthy liver should be presented at a specialized hepatobiliary unit. Thromboembolism might be an early paraneoplastic symptom and needs to be elucidated further in the context of FL-HCC.
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Affiliation(s)
- Anastasia Lemekhova
- Department of General, Visceral, and Transplantation Surgery, Ruprecht Karls University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.,Liver Cancer Centre Heidelberg (LCCH), Heidelberg, Germany
| | - Daniel Hornuss
- Liver Cancer Centre Heidelberg (LCCH), Heidelberg, Germany.,Department of Gastroenterology and Hepatology, Ruprecht Karls University Hospital, Heidelberg, Germany
| | - Georgios Polychronidis
- Department of General, Visceral, and Transplantation Surgery, Ruprecht Karls University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.,Liver Cancer Centre Heidelberg (LCCH), Heidelberg, Germany
| | - Philipp Mayer
- Liver Cancer Centre Heidelberg (LCCH), Heidelberg, Germany.,Department of Diagnostic and Interventional Radiology, Ruprecht Karls University Hospital, Heidelberg, Germany
| | - Christian Rupp
- Department of Gastroenterology and Hepatology, Ruprecht Karls University Hospital, Heidelberg, Germany
| | - Thomas Longerich
- Liver Cancer Centre Heidelberg (LCCH), Heidelberg, Germany.,Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Karl-Heinz Weiss
- Liver Cancer Centre Heidelberg (LCCH), Heidelberg, Germany.,Department of Gastroenterology and Hepatology, Ruprecht Karls University Hospital, Heidelberg, Germany
| | - Markus Büchler
- Department of General, Visceral, and Transplantation Surgery, Ruprecht Karls University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.,Liver Cancer Centre Heidelberg (LCCH), Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral, and Transplantation Surgery, Ruprecht Karls University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.,Liver Cancer Centre Heidelberg (LCCH), Heidelberg, Germany
| | - Katrin Hoffmann
- Department of General, Visceral, and Transplantation Surgery, Ruprecht Karls University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. .,Liver Cancer Centre Heidelberg (LCCH), Heidelberg, Germany.
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46
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McDonald JD, Hernandez JM. ASO Author Reflections: Fibrolamellar Hepatocellular Carcinoma and Alpha-Fetoprotein. Ann Surg Oncol 2020; 27:1906-1907. [PMID: 32189170 DOI: 10.1245/s10434-020-08366-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Indexed: 11/18/2022]
Affiliation(s)
- James D McDonald
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jonathan M Hernandez
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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McDonald JD, Gupta S, Shindorf ML, Gamble LA, Ruff SM, Drake J, Heller T, Wan JY, Dickson PV, Glazer ES, Davis JL, Deneve JL, Hernandez JM. Elevated Serum α-Fetoprotein is Associated with Abbreviated Survival for Patients with Fibrolamellar Hepatocellular Carcinoma Who Undergo a Curative Resection. Ann Surg Oncol 2020; 27:1900-1905. [PMID: 31925595 DOI: 10.1245/s10434-019-08178-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Fibrolamellar hepatocellular carcinoma (FLC) is a rare variant of hepatocellular carcinoma (HCC), with most clinical data stemming from single-institution series. The variability in the literature lends support for analysis using a large national dataset. In doing so, we sought to (1) define the characteristics and outcomes of patients with FLC; (2) determine factors associated with survival in patients undergoing resection; and (3) compare the overall survival (OS) of patients with FLC with a matched group of patients with HCC. METHODS The National Cancer Database was queried for patients with FLC, and their clinicopathologic features were recorded. Univariate and multivariate analyses were performed to delineate factors associated with survival. RESULTS Between 2004 and 2015, 496 patients were diagnosed with FLC, 229 of whom underwent a curative resection. The median OS for patients with FLC undergoing curative resection was 78.5 months. Factors associated with abbreviated OS in this surgical cohort include multiple tumors [hazard ratio (HR) 3.15, p = 0.025], positive regional lymph nodes (HR 2.83, p = 0.023), and elevated serum α-fetoprotein (AFP; HR 2.81, p = 0.034). When the OS of patients with FLC was compared with a matched group of patients with HCC, no difference was detected (p = 0.748); however, patients with FLC and elevated AFP had abbreviated OS compared with patients with HCC and elevated AFP (43 vs. 82 months, p ≤ 0.001). CONCLUSIONS Elevations in serum AFP occur more frequently than previously documented for patients with FLC and are associated with abbreviated OS. AFP levels may help guide the decision for operative intervention in patients with FLC.
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Affiliation(s)
- James D McDonald
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Shreya Gupta
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Mackenzie L Shindorf
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Lauren A Gamble
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Samantha M Ruff
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Justin Drake
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Theo Heller
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Jim Y Wan
- Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Paxton V Dickson
- Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Evan S Glazer
- Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Jeremy L Davis
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jeremiah L Deneve
- Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Jonathan M Hernandez
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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Lafaro KJ, Eng OS, Raoof M, Ituarte P, Warner SG, Singh G, Fong Y, Melstrom LG. A prognostic nomogram for patients with resected fibrolamellar hepatocellular carcinoma. Hepatobiliary Surg Nutr 2019; 8:338-344. [PMID: 31489303 DOI: 10.21037/hbsn.2019.05.03] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background Fibrolamellar hepatocellular carcinoma (FLHC) is a unique entity compared to conventional hepatocellular carcinoma. The aim of this study was to examine post-resection outcomes and prognostic indicators for survival in this group of FLHC patients. Methods A retrospective analysis of the National Cancer Database (NCDB) for patients with FLHC who underwent resection from 2004 to 2014 was performed. Univariate and multivariate Cox proportional hazard models were used to identify factors associated with overall survival, and a prognostic nomogram was generated. Results There were 197 patients identified, 171 (86.8%) of whom had long-term follow-up data. Univariate and multivariate analyses were performed using patient and tumor demographics with the outcome variable of overall survival. On multivariate analysis, age [hazard ratio (HR) 1.03, P=0.003], vascular invasion (HR 1.75, P=0.05), tumor size >7 cm (HR 2.18, P=0.044), multifocal disease (HR 3.34, P=0.002), and node positive (pN+) disease (HR 2.75, P=0.003) were all negative predictors of overall survival. A prognostic nomogram was generated using these factors with a c-statistic superior to that of American Joint Committee on Cancer (AJCC) staging (0.710 vs. 0.654). Conclusions Independent predictors of decreased overall survival in patients with FLHC include age, vascular invasion, tumor size >7 cm, multifocal disease, and pN+ disease. This is the first study to develop a nomogram exclusively for FLHC that may predict survival in future studies.
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Affiliation(s)
- Kelly J Lafaro
- Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | - Oliver S Eng
- Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | - Mustafa Raoof
- Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | - Philip Ituarte
- Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | - Susanne G Warner
- Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | - Gagandeep Singh
- Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | - Yuman Fong
- Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | - Laleh G Melstrom
- Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
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Zakka K, Jiang R, Alese OB, Shaib WL, Wu C, Wedd JP, Sellers MT, Behera M, El-Rayes BF, Akce M. Clinical outcomes of rare hepatocellular carcinoma variants compared to pure hepatocellular carcinoma. J Hepatocell Carcinoma 2019; 6:119-129. [PMID: 31413960 PMCID: PMC6660638 DOI: 10.2147/jhc.s215235] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 06/26/2019] [Indexed: 12/12/2022] Open
Abstract
Background HCC variants are rare primary hepatic tumors. The aim of this study is to compare clinical characteristics and outcomes of HCC variants with pure HCC. Methods Patients diagnosed between 2004 and 2013 with ICD-O-3 8180/3 and 8170/3-8175/3 were identified from the National Cancer Database. Univariate and multivariate survival analyses were conducted to analyze the association between histology and overall survival (OS). Results 80,280 patients were identified; pure HCC 78,461 (97.7%), fibrolamellar (FLHCC) 310 (0.4%), scirrhous 161 (0.2%), spindle cell 72 (0.1%), clear cell 487 (0.6%), pleomorphic 23 (0.0%), and combined HCC and cholangiocarcinoma (mixed HCC) 766 (1.0%). 76.7% were male and 72% Caucasian. Liver transplant was performed in 10.1% of pure HCC, 14.5% of mixed HCC, 16.2% of scirrhous, 6.9% of spindle cell, 8.8% of clear cell, 8.7% of pleomorphic, and 3.2% of FLHCC (p<0.001). Pure HCC (10.6%) underwent surgical resection without transplant less often than variants except for scirrhous (9.9%) (p<0.001). More than a third of patients in each histological type received chemotherapy. FLHCC had the best 5-year OS (38.7%), spindle cell and pleomorphic had the worst (9.6% and 13.0%). In multivariate analysis stratified by histology variants, chemotherapy was associated with improved OS in all histologies except for scirrhous and pleomorphic HCC. Conclusion HCC variants underwent surgical resection more often than pure HCC. FLHCC had the best 5-year OS. Liver transplant was commonly performed in HCC variants.
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Affiliation(s)
- Katerina Zakka
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Renjian Jiang
- Department of Research Informatics, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Olatunji B Alese
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Walid L Shaib
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Christina Wu
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Joel P Wedd
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Marty T Sellers
- Division of General and GI Surgery, Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA
| | - Madhusmita Behera
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.,Department of Research Informatics, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Bassel F El-Rayes
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Mehmet Akce
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
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Zhou R, Lu D, Li W, Tan W, Zhu S, Chen X, Min J, Shang C, Chen Y. Is lymph node dissection necessary for resectable intrahepatic cholangiocarcinoma? A systematic review and meta-analysis. HPB (Oxford) 2019; 21:784-792. [PMID: 30878490 DOI: 10.1016/j.hpb.2018.12.011] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Revised: 12/06/2018] [Accepted: 12/11/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND The objective of this meta-analysis was to evaluate the effectiveness and safety of lymph node dissection (LND) in patients with intrahepatic cholangiocarcinoma (ICC). METHODS A literature search with a date range of January 2000 to January 2018 was performed to identify studies comparing lymph node dissection (LND+) with non-lymph node dissection (LND-) for patients with ICC. The LND + group was further divided into positive (LND + N+) and negative (LND + N-) lymph node status groups based on pathological analysis. RESULTS 13 studies including 1377 patients were eligible. There were no significant differences in overall survival (OS) (HR 1.13, 95% CI 0.94-1.36; P = 0.20), disease-free survival (DFS) (HR 1.23, 95% CI 0.94-1.60; P = 0.13), or recurrence (OR 1.39, 95% CI 0.90-2.15; P = 0.14) between LND + group and LND-group. Postoperative morbidity was significantly higher in the LND + group (OR 2.67, 95% CI 1.74-4.10; P < 0.001). A subset analysis showed that OS was similar between LND + N- and LND-groups (HR 1.13, 95% CI 0.82-1.56; P = 0.450). However when comparing, OS of the LND-group to the LND+N+ group there was a significant increase in OS for the LND-group (HR 3.26, 95% CI 1.85-5.76; P < 0.001). CONCLUSIONS LND does not seem to positively affect overall survival and is associated with increased post-operative morbidity.
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Affiliation(s)
- Rui Zhou
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Dihan Lu
- Department of Anesthesiology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Wenda Li
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Wenliang Tan
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Sicong Zhu
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xianqing Chen
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jun Min
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
| | - Changzhen Shang
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
| | - Yajin Chen
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
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