411 results on '"Fibrolamellar carcinoma"'
Search Results
2. Sapanisertib and Ziv-Aflibercept in Treating Patients With Recurrent Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
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- 2024
3. Neratinib Alone or in Combination with Immune Checkpoint Inhibitors with or without Mammalian Target of Rapamycin Inhibitors in Patients with Fibrolamellar Carcinoma
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Ghassan K. Abou-Alfa, Tim Meyer, Richard Kinh Gian Do, Sarina A. Piha-Paul, Joseph S. Light, Scott Sherrin, Amin Yaqubie, Alison Clemens O’Neill, James J. Harding, Raed Al-Rajabi, Crystal S. Denlinger, Pablo Cano, Albert S. Cornelius, Eileen M. O'Reilly, Daniel DiPrimeo, Lisa D. Eli, John D. Gordan, and David B. Solit
- Subjects
neratinib ,fibrolamellar carcinoma ,summit phase 2 basket study ,pan-her kinase inhibition ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - 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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- 2024
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4. Safety and Efficacy of Cyclophosphamide, Sorafenib, Bevacizumab, and Atezolizumab in Pediatric Solid Tumor Patients
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- 2023
5. KAT-101 in Subjects With Hepatocellular Carcinoma (HCC)
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- 2023
6. Fc-Engineered Anti-CTLA-4 Monoclonal Antibody in Advanced Cancer
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- 2023
7. Checkpoint Inhibition In Pediatric Hepatocellular Carcinoma
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Allison O'Neill, MD, Sponsor Investigator
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- 2023
8. Treatment Outcomes in Patients with Advanced Fibrolamellar Hepatocellular Carcinoma Under Systemic Treatment: Analysis of Clinical Characteristics, Management, and Radiomics
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Da Fonseca LG, Yamamoto VJ, Trinconi Cunha M, Torre GS, Araujo RL, Fonseca GM, Chen ATC, Chagas AL, Herman P, Alves VAF, and Carrilho FJ
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liver cancer ,systemic treatment ,radiomics ,fibrolamellar carcinoma ,rare tumors. ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Leonardo G Da Fonseca,1,* Victor Junji Yamamoto,1,* Mateus Trinconi Cunha,1 Giovanna Sawaya Torre,2 Raphael LC Araujo,3 Gilton Marques Fonseca,4 Andre Tsin Chih Chen,5 Aline Lopes Chagas,6 Paulo Herman,4 Venancio Avancini Ferreira Alves,7 Flair Jose Carrilho6 1Department 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; 2Department of Radiology, ICESP - Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil; 3Digestive Surgery Division, Department of Surgery, Universidade Federal de São Paulo, São Paulo, Brazil; 4Digestive Surgery Division, Department of Gastroenterology, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil; 5Radiation Oncology Department - Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil; 6Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil; 7Department of Pathology, LIM-14, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil*These authors contributed equally to this workCorrespondence: 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, Avenida Dr Arnaldo, 251, 5th Floor ZIP: 01246-000, São Paulo, Brazil, Tel/Fax +55 11 3893-2000, Email l.fonseca@fm.usp.brPurpose: 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.Keywords: liver cancer, systemic treatment, radiomics, fibrolamellar carcinoma, rare tumors
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- 2023
9. Study of (1) Everolimus, (2) Estrogen Deprivation Therapy (EDT) With Leuprolide + Letrozole and (3) Everolimus + EDT in Patients With Unresectable Fibrolamellar Hepatocellular Carcinoma (FLL-HCC)
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The Fibrolamellar Cancer Foundation, Dana-Farber Cancer Institute/Brigham and Women¹s Cancer Center and Massachusetts General Hospital Cancer Center, Johns Hopkins University, University of California, San Francisco, Abbott, and Novartis Pharmaceuticals
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- 2022
10. Evaluation of Protein Kinase cAMP-Activated Catalytic Subunit Alpha as a Therapeutic Target for Fibrolamellar Carcinoma
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Stefanie S. Schalm, Erin O’Hearn, Kevin Wilson, Timothy P. LaBranche, Grace Silva, Zhuo Zhang, Lucian DiPietro, Neil Bifulco, Richard Woessner, Nicolas Stransky, Darshan Sappal, Robert Campbell, Riadh Lobbardi, Michael Palmer, Joseph Kim, Chaoyang Ye, Marion Dorsch, Christoph Lengauer, Timothy Guzi, Vivek Kadambi, Andrew Garner, and Klaus P. Hoeflich
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Fibrolamellar carcinoma ,PRKACA ,DNAJB1-PRKACA ,Kinase inhibitor ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background and Aims: Fibrolamellar carcinoma (FLC) is a rare, difficult-to-treat liver cancer primarily affecting pediatric and adolescent patients, and for which precision medicine approaches have historically not been possible. The DNAJB1-PRKACA gene fusion was identified as a driver of FLC pathogenesis. We aimed to assess whether FLC tumors maintain dependency on this gene fusion and determine if PRKACA is a viable therapeutic target. Methods: FLC patient-derived xenograft (PDX) shRNA cell lines were implanted subcutaneously into female NOD-SCID mice and tumors were allowed to develop prior to randomization to doxycycline (to induce knockdown) or control groups. Tumor development was assessed every 2 days. To assess the effect of treatment with novel selective PRKACA small molecule kinase inhibitors, BLU0588 and BLU2864, FLC PDX tumor cells were implanted subcutaneously into NOD-SCID mice and tumors allowed to develop. Mice were randomized to treatment (BLU0588 and BLU2864, orally, once daily) or control groups and tumor size determined as previously. Results: Knockdown of DNAJB1-PRKACA reversed a FLC-specific gene signature and reduced PDX tumor growth in mice compared to the control group. Furthermore, FLC PDX tumor growth was significantly reduced with BLU0588 and BLU2864 treatment vs control (P = .003 and P = .0005, respectively). Conclusion: We demonstrated, using an inducible knockdown and small molecule approaches, that FLC PDX tumors were dependent upon DNAJB1-PRKACA fusion activity. In addition, this study serves as a proof-of-concept that PRKACA is a viable therapeutic target for FLC and warrants further investigation.
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- 2023
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11. Phase Separation of a PKA Regulatory Subunit Controls cAMP Compartmentation and Oncogenic Signaling
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Zhang, Jason Z, Lu, Tsan-Wen, Stolerman, Lucas M, Tenner, Brian, Yang, Jessica R, Zhang, Jin-Fan, Falcke, Martin, Rangamani, Padmini, Taylor, Susan S, Mehta, Sohum, and Zhang, Jin
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Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Carcinogenesis ,Carcinoma ,Hepatocellular ,Cell Compartmentation ,Cell Line ,Tumor ,Cell Proliferation ,Cyclic AMP ,Cyclic AMP-Dependent Protein Kinase RIalpha Subunit ,Cyclic AMP-Dependent Protein Kinases ,Cytoplasm ,HSP40 Heat-Shock Proteins ,Humans ,Liver Neoplasms ,Mice ,Oncogenes ,Protein Domains ,Rats ,Rats ,Sprague-Dawley ,Recombinant Fusion Proteins ,Signal Transduction ,Spectroscopy ,Fourier Transform Infrared ,Time-Lapse Imaging ,DnaJB1-PKA ,FLC ,FRET ,biosensor ,fibrolamellar carcinoma ,live cell imaging ,membraneless organelle ,signal transduction ,split GFP ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
The fidelity of intracellular signaling hinges on the organization of dynamic activity architectures. Spatial compartmentation was first proposed over 30 years ago to explain how diverse G protein-coupled receptors achieve specificity despite converging on a ubiquitous messenger, cyclic adenosine monophosphate (cAMP). However, the mechanisms responsible for spatially constraining this diffusible messenger remain elusive. Here, we reveal that the type I regulatory subunit of cAMP-dependent protein kinase (PKA), RIα, undergoes liquid-liquid phase separation (LLPS) as a function of cAMP signaling to form biomolecular condensates enriched in cAMP and PKA activity, critical for effective cAMP compartmentation. We further show that a PKA fusion oncoprotein associated with an atypical liver cancer potently blocks RIα LLPS and induces aberrant cAMP signaling. Loss of RIα LLPS in normal cells increases cell proliferation and induces cell transformation. Our work reveals LLPS as a principal organizer of signaling compartments and highlights the pathological consequences of dysregulating this activity architecture.
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- 2020
12. Tumors of the Liver
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Bergasa, Nora V. and Bergasa, Nora V., editor
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- 2022
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13. A Multidisciplinary Approach to the Management of Fibrolamellar Carcinoma: Current Perspectives and Future Prospects
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Polychronidis G, Murtha-Lemekhova A, Fuchs J, Karathanasi E, and Hoffmann K
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hepatocellular carcinoma ,fibrolamellar carcinoma ,tumor recurrence ,liver resection ,surgery ,transarterial radioembolization ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Georgios Polychronidis,1,* Anastasia Murtha-Lemekhova,1,* Juri Fuchs,1 Evdokia Karathanasi,2 Katrin Hoffmann1 1Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Heidelberg, 69120, Germany; 2Post-Graduate Program “Human Genetics- Genetic Counseling”, Faculty of Medicine, University of Thessaly, Larisa, Greece*These authors contributed equally to this workCorrespondence: Katrin Hoffmann, Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, Heidelberg, 69120, Germany, Email katrin.hoffmann@med.uni-heidelberg.deAbstract: 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.Keywords: hepatocellular carcinoma, fibrolamellar carcinoma, tumor recurrence, liver resection, surgery, transarterial radioembolization
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- 2022
14. Prognostic value of the proportion of the sclerosing component in fibrolamellar liver carcinoma
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E. Yu. Antonova, E. A. Moroz, D. V. Podluzhny, N. E. Kudashkin, I. A. Dzhanyan, A. Yu. Volkov, K. K. Laktionov, and V. V. Breder
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fibrolamellar carcinoma ,liver tumor ,prognosis ,sclerosing component ,microvascular invasion ,Medicine - Abstract
Introduction. Fibrolamellar hepatocellular carcinoma (FLC), which develops most often in the younger population. In FLC, variable histoarchitectonics are noted, possibly the presence of a sclerosing component, foci of necrosis and dystrophy of tumor cells.Objective. Assessment of the influence of the proportion of the sclerosing component in fibrolamellar carcinoma (FLC) of the liver on the course and prognosis of the disease. Determination of the relationship between the proportion of the sclerosing component in the tumor and the frequency of microvascular invasion.Materials and methods. A retrospective study included 34 patients with a diagnosis of FLC, who underwent radical surgical treatment at the first stage. A histological assessment of the proportion (%) of the sclerosing component in FLC was made. The effect of the proportion of the sclerosing component on overall (OS) and relapse-free (DFS) survival was assessed. The analysis of the relationship between the proportion of the sclerosing component in the tumor and the frequency of microvascular invasion was carried out.Results. Significantly worse RFS was achieved in the groups of patients with a sclerosing component in FLC > 5% than in the group of patients with a sclerosing component in FLC ≤ 5% (p = 0.0010; p = 0.024; log – rank test). Median DDS in group 1 is 107 (95% CI, 22–192) months; at 2 – 11 (95% CI, 8–14) months; in 3 – 21 (95% CI, 8–33). The frequency of histologically confirmed microvascular invasion in the compared groups was 29, 74, 87.5%, respectively. OS was significantly worse in 2 groups (27 patients in total) with a sclerosing component in FLC > 5% than in the group of patients with a sclerosing component in FLC ≤ 5%. Median OS in group 1 120 (95% CI, 60–180) months; at 2 – 41 (95% CI, 15–92) months; in 3 – 69 (95% CI, 35–103). A direct relationship was found between an increase in the proportion of the sclerosing component in a tumor and an increase in the frequency of microvascular invasion.Conclusions. We can assume that the severity of the sclerosing component in the FLK tumor can serve as an effective morphological marker of a less favorable prognosis for this HCC subtype and correlate with the frequency of microvascular invasion.
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- 2021
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15. Successful Liver Transplantation of Recurrent Fibrolamellar Carcinoma following Clinical and Pathologic Complete Response to Triple Immunochemotherapy: A Case Report.
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Kang, Sandra, Magliocca, Joseph, Sellers, Marty, Roccaro, Giorgio, Zheng, Wei, Pectasides, Melina, Draper, Amber, Guadagno, Jessica, El-Rayes, Bassel, and Akce, Mehmet
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- *
LIVER transplantation , *IMMUNE checkpoint inhibitors , *CANCER chemotherapy , *GENE fusion , *WATCHFUL waiting - 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 × 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. [ABSTRACT FROM AUTHOR]
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- 2022
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16. Prognostic Role of Lymph Node Sampling in Adolescent and Young Adults With Fibrolamellar Carcinoma.
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Schultz, Susan P., Holtestaul, Torbjorg, Marenco, Christopher W., Bader, Julia O., Horton, John D., and Nelson, Daniel W.
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YOUNG adults , *LYMPH nodes , *LUPUS nephritis , *TEENAGERS , *CARCINOMA , *SURVIVAL analysis (Biometry) - Abstract
Hepatocellular carcinoma (HCC) is rare among adolescent and young adult (AYA) patients, and resection or transplant remains the only curative therapy. The role of lymph node (LN) sampling is not well-defined. The aim of this study was to describe practice patterns, as well as investigate the impact of LN sampling on survival outcomes in this population. A retrospective cohort study using the 2004-2018 National Cancer Database (NCDB) was performed. Patients ≤21 y old with nonmetastatic HCC who underwent liver resection or transplant were evaluated. Clinical features of patients who underwent LN sampling were compared to those who did not, and univariable and multivariable logistic regression was performed to evaluate independent predictive factors of node positivity. Survival analysis was performed using Kaplan–Meier methods and Cox Proportional Hazard Survival Regression. A total of 262 AYA patients with HCC were identified, of whom 137 (52%) underwent LN sampling, 44 patients had positive nodes, 40 (95%) of them had tumors >5 cm; 87 (64%) of patients with sampled nodes had fibrolamellar carcinoma (FLC), which was an independent risk factor for predicting positive nodes (P = 0.001). There was no difference in overall survival between patients who underwent LN sampling and those who did not; however, 5-y overall survival for node-positive patients was 40% versus 79% for node-negative patients (P < 0.0001). In AYA patients with HCC, LN sampling was not associated with an independent survival benefit. However, FLC was an independent risk factor for LN positivity, suggesting a role for routine LN sampling in these patients. [ABSTRACT FROM AUTHOR]
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- 2022
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17. Proteo-metabolomics and patient tumor slice experiments point to amino acid centrality for rewired mitochondria in fibrolamellar carcinoma.
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Long D Jr, Chan M, Han M, Kamdar Z, Ma RK, Tsai PY, Francisco AB, Barrow J, Shackelford DB, Yarchoan M, McBride MJ, Orre LM, Vacanti NM, Gujral TS, and Sethupathy P
- Abstract
Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLC's potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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18. Fibrolamellar Carcinoma
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Thompson, Scott M., Torbenson, Michael S., Roberts, Lewis R., Venkatesh, Sudhakar K., Roberts, Lewis R., editor, Yang, Ju Dong, editor, and Venkatesh, Sudhakar K., editor
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- 2020
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19. Fibrolamellar Carcinoma with DNAJB1-PRKACA Fusion in a 16-Year-Old: Case Report and Review of Literature
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Varsha Prakash and Neha Varshney
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DNAJB1-PRKACA fusion ,fibrolamellar carcinoma ,hepatocellular carcinoma ,mixed fibrolamellar hepatocellular carcinoma ,PRKACA rearrangement ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Fibrolamellar hepatocellular carcinoma (FLC) is a unique primary liver malignancy arising in noncirrhotic livers of young adults with an incidence of 0.02 per 100,000 in the USA (1). In the 5th edition of the WHO classification of the digestive system tumors published in 2019, fibrolamellar carcinoma is categorized as a subset of hepatocellular carcinoma (HCC). In 2014, the unique DNAJB1-PRKACA chimeric fusion protein was identified. Later studies proved this chimeric fusion protein as the main pathological driver in the disease manifestation of fibrolamellar carcinoma. Despite the invention of specific molecular genetic alteration in FLC, its oncogenic role and implication in FLC treatment remain an enigma. Surgical resection remains the primary therapeutic option, and the recurrence rate is extremely high (1). We present a case of fibrolamellar carcinoma in a pediatric patient with the PRKACA rearrangement resulting in DNAJB1-PRKACA fusion.
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- 2022
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20. Epidemiological and Clinical Characteristics of Five Rare Pathological Subtypes of Hepatocellular Carcinoma.
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Chen, Xiaoyuan, Lu, Yiwei, Shi, Xiaoli, Han, Guoyong, Zhang, Long, Ni, Chuangye, Zhao, Jie, Gao, Yun, and Wang, Xuehao
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HEPATOCELLULAR carcinoma ,RECEIVER operating characteristic curves ,TIBIAL plateau fractures ,AKAIKE information criterion - Abstract
Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor with several rare pathological subtypes and which is still poorly understood. This study aimed to describe the epidemiological and clinical spectrum of five rare HCC subtypes and develop a competing risk nomogram for cancer-specific survival prediction. Methods: The study cohort was recruited from the Surveillance, Epidemiology, and End Results database. The clinicopathological data of 50,218 patients histologically diagnosed with classic HCC and five rare subtypes (ICD-O-3 Histology Code = 8170/3-8175/3) between 2004 and 2018 were reviewed. The annual percent change (APC) was calculated utilizing Joinpoint regression. The nomogram was developed based on multivariable competing risk survival analyses. Akaike information criterion, Bayesian information criterion, C-index, calibration curve, and area under the receiver operating characteristic curve were obtained to evaluate the prognostic performance. A decision curve analysis was introduced to examine the clinical value of the models. Results: Despite scirrhous carcinoma, which showed a decreasing trend (APC = -6.8%, P = 0.025), the morbidity of other rare subtypes remained stable from 2004 to 2018. The incidence-based mortality was plateau in all subtypes during the period. Clear cell carcinoma is the most common subtype (n = 551, 1.1%), followed by subtypes of fibrolamellar (n = 241, 0.5%), scirrhous (n = 82, 0.2%), spindle cell (n = 61, 0.1%), and pleomorphic (n = 17, ~0%). The patients with fibrolamellar carcinoma were younger and more likely to have a non-cirrhotic liver and better prognoses. Scirrhous carcinoma shared almost the same macro-clinical characteristics and outcomes as the classic HCC. Clear cell carcinoma tended to occur in the Asia-Pacific elderly male population, and more than half of them were large HCC (Size>5cm). Sarcomatoid (including spindle cell and pleomorphic) carcinoma was associated with a larger tumor size, poorer differentiation, and more dismal prognoses. The pathological subtype, T stage, M stage, surgery, alpha-fetoprotein, and cancer history were confirmed as the independent predictors in patients with rare subtypes. The nomogram showed good calibration, discrimination, and net benefits in clinical practice. Conclusion: The rare subtypes had unique clinicopathological features and biological behaviors compared with the classic HCC. Our findings could provide a valuable reference for clinicians. The constructed nomogram could predict the prognoses with good performance, which is meaningful to individualized management. [ABSTRACT FROM AUTHOR]
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- 2022
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21. Reports from University of Cape Town Advance Knowledge in Fibrolamellar Carcinoma (Liver Resection for Hepatocellular and Fibrolamellar Carcinoma In a South African Tertiary Referral Centre - an Observational Cohort Analysis).
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REPORTERS & reporting ,OVERALL survival ,ELECTRONIC records ,SURGICAL excision ,SURVIVAL rate ,LIVER surgery - Abstract
A recent report from the University of Cape Town in South Africa highlights the challenges faced in the treatment of hepatocellular carcinomas (HCC) and fibrolamellar carcinoma (FLC) in sub-Saharan Africa. The study analyzed the outcomes of liver resections for HCC and FLC at a tertiary referral center in South Africa. The results showed that while liver resection was safe with no mortality, one-third of patients experienced postoperative complications. Additionally, the study found a high recurrence rate, which remains a significant obstacle to achieving better survival outcomes. [Extracted from the article]
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- 2024
22. Epidemiological and Clinical Characteristics of Five Rare Pathological Subtypes of Hepatocellular Carcinoma
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Xiaoyuan Chen, Yiwei Lu, Xiaoli Shi, Guoyong Han, Long Zhang, Chuangye Ni, Jie Zhao, Yun Gao, and Xuehao Wang
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hepatocellular carcinoma ,pathological subtype ,fibrolamellar carcinoma ,scirrhous carcinoma ,clear cell carcinoma ,spindle cell carcinoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundHepatocellular carcinoma (HCC) is a highly heterogeneous tumor with several rare pathological subtypes and which is still poorly understood. This study aimed to describe the epidemiological and clinical spectrum of five rare HCC subtypes and develop a competing risk nomogram for cancer-specific survival prediction.MethodsThe study cohort was recruited from the Surveillance, Epidemiology, and End Results database. The clinicopathological data of 50,218 patients histologically diagnosed with classic HCC and five rare subtypes (ICD-O-3 Histology Code = 8170/3-8175/3) between 2004 and 2018 were reviewed. The annual percent change (APC) was calculated utilizing Joinpoint regression. The nomogram was developed based on multivariable competing risk survival analyses. Akaike information criterion, Bayesian information criterion, C-index, calibration curve, and area under the receiver operating characteristic curve were obtained to evaluate the prognostic performance. A decision curve analysis was introduced to examine the clinical value of the models.ResultsDespite scirrhous carcinoma, which showed a decreasing trend (APC = -6.8%, P = 0.025), the morbidity of other rare subtypes remained stable from 2004 to 2018. The incidence-based mortality was plateau in all subtypes during the period. Clear cell carcinoma is the most common subtype (n = 551, 1.1%), followed by subtypes of fibrolamellar (n = 241, 0.5%), scirrhous (n = 82, 0.2%), spindle cell (n = 61, 0.1%), and pleomorphic (n = 17, ~0%). The patients with fibrolamellar carcinoma were younger and more likely to have a non-cirrhotic liver and better prognoses. Scirrhous carcinoma shared almost the same macro-clinical characteristics and outcomes as the classic HCC. Clear cell carcinoma tended to occur in the Asia-Pacific elderly male population, and more than half of them were large HCC (Size>5cm). Sarcomatoid (including spindle cell and pleomorphic) carcinoma was associated with a larger tumor size, poorer differentiation, and more dismal prognoses. The pathological subtype, T stage, M stage, surgery, alpha-fetoprotein, and cancer history were confirmed as the independent predictors in patients with rare subtypes. The nomogram showed good calibration, discrimination, and net benefits in clinical practice.ConclusionThe rare subtypes had unique clinicopathological features and biological behaviors compared with the classic HCC. Our findings could provide a valuable reference for clinicians. The constructed nomogram could predict the prognoses with good performance, which is meaningful to individualized management.
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- 2022
- Full Text
- View/download PDF
23. Fibrolamellar Carcinoma: A Multimodal Approach
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João Vasco Barreira, Nádia Silva, Anuraj Parmanande, Manuel Rocha, João S. Coelho, Hugo Pinto Marques, and Ricardo da Luz
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oncology ,fibrolamellar carcinoma ,rare tumors ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Fibrolamellar carcinoma is a rare variant of hepatocellular carcinoma not associated with cirrhosis or viral hepatitis. Serum alpha-fetoprotein levels are usually normal; the histology is of a well-differentiated tumor, and the staging is the same as for hepatocellular carcinoma. We describe the case of a female patient in her 4th decade of life with a diagnosis of fibrolamellar hepatocellular carcinoma with a multimodal approach. The rare incidence of this cancer and its unusual clinical presentation justifies reporting this case and highlights the importance of multidisciplinary teams in the treatment of cancer patients.
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- 2020
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24. A rare case of metastatic ectopic fibrolamellar hepatocellular carcinoma in a young healthy patient: A case report
- Author
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Jasmin Hundal, M.D., M.S., Anagha Nagaraj, M.D., Abigael Luke, M.D., and James Vredenburgh, M.D.
- Subjects
Fibrolamellar carcinoma ,Extrahepatic liver tissue ,Hepatocellular carcinoma ,Hepatic malignancy ,Case report ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Extrahepatic tissue is liver parenchyma that develops in other organs but retains the general morphology and/or functionality of the hepatocytes within the mother liver, including the potential for neoplastic transformation. The conversion of an ectopic liver to a malignant tissue is an extremely rare finding.We present a 30-year-old male with no past medical history who presented with altered mental status and upon further inquiring admitted to progressive abdominal discomfort, fullness, early satiety, night sweats and weight loss. Contrast-enhanced CT imaging of his abdomen and pelvis demonstrated a large intra-abdominal mass with significant mass effect on the liver. Subsequently, patient underwent a CT-guided biopsy of the intra-abdominal mass and histological features of the specimen were consistent with fibrolamellar hepatocellular carcinoma.Here, we report a rare case of metastatic fibrolamellar hepatocellular carcinoma originating in a focus of extrahepatic liver tissue located in the pancreas. The tumor was found incidentally on imaging and was associated with liver synthetic dysfunction but no elevation of alpha-fetoprotein levels carcinoma in a young patient without any prior medical history. This case is unique in that it highlights a more severe outcome of this rare tumor type and underscores the need for accurate and timely diagnosis and treatment. It discusses the treatment with bevacizumab and atezolizumab. While prior case reports typically describe surgical resection of the tumor given its limited location to the ectopic foci, our patient presented with extensive metastatic disease and was treated with immunotherapy and anti-angiogenic therapy followed by chemotherapy which ultimately did not slow the progression of his disease.
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- 2021
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25. A Case of a Boy With Undiagnosed Fibrolamellar Carcinoma Who Died Due to Severe Hemorrhage From Diaphragm.
- Author
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Naito H, Chang Y, Nitta K, Kadota E, and Kakiuchi Y
- Abstract
An 11-year-old boy presented with vomiting and abdominal pain. Ultrasonography and blood tests revealed no abnormalities. He was diagnosed with viral gastroenteritis; however, the following morning, he was found dead in bed. Postmortem examination revealed that a 1,900 mL hemorrhage with strong coagulation from the diaphragm was the cause of death. He had no traumatic episodes, injuries, or a medical history of hemorrhagic diathesis. The presence of a fibrin-like clot indicated coagulation activation; however, most criteria for disseminated intravascular coagulation were not observed. Fibrolamellar carcinoma, a rare hepatocellular carcinoma, was found; however, liver disorder was not estimated based on the pathological findings. In conclusion, the mechanism of hemorrhage could not be explained. Although we were unable to identify the cause of the hemorrhage, we could not completely rule out the possibility that fibrolamellar carcinoma had an unknown influence on the hemorrhage. Given the limited number of studies on fibrolamellar carcinoma, we present a case of a boy with undiagnosed fibrolamellar carcinoma who died due to severe hemorrhage., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Naito et al.)
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- 2024
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26. Fibrolamellar Carcinoma: A Rare Liver Neoplasm.
- Author
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Apumayta ED, Kahlam A, and Ruiz EF
- 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., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Apumayta et al.)
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- 2024
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27. Reports Outline Fibrolamellar Carcinoma Findings from St. Jude Children's Research Hospital (Dnajb1-prkaca Fusion Neoantigens Elicit Rare Endogenous T Cell Responses That Potentiate Cell Therapy for Fibrolamellar Carcinoma).
- Abstract
A recent report from St. Jude Children's Research Hospital discusses the potential for immunotherapy as a treatment option for fibrolamellar carcinoma (FLC), a liver tumor with limited treatment options and high mortality rates. The report focuses on a driver mutation in FLC known as the DNAJB1-PRKACA gene fusion, which could be a target for immunotherapy. The study found that fusion-specific CD8 T cells are rare in FLC patients, but identified two functional fusion-specific T cell receptors (TCRs) that showed anti-tumor activity. These findings provide insights into the potential development of immunotherapies for FLC. [Extracted from the article]
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- 2024
28. Mitochondrial Calcium Signaling Regulates Branched-Chain Amino Acid Catabolism in Fibrolamellar Carcinoma.
- Subjects
MITOCHONDRIA ,CATABOLISM ,CARCINOMA ,CALCIUM ,TRANSCRIPTION factors - Abstract
A preprint abstract from biorxiv.org discusses the role of mitochondrial calcium signaling in regulating branched-chain amino acid catabolism in fibrolamellar carcinoma (FLC), a type of liver cancer. The study found that loss of uniporter function, which regulates metabolic homeostasis, increases the expression of proteins in the BCAA catabolism pathway. Conversely, FLC, which has high mitochondrial calcium levels, suppresses the expression of BCAA catabolism enzymes. The study also identifies the transcription factor KLF15 as a key regulator in this process. However, it is important to note that this preprint has not been peer-reviewed. [Extracted from the article]
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- 2024
29. New Findings on Fibrolamellar Carcinoma Described by Investigators at Cornell University (Dnajb1-prkaca Fusion Protein-regulated Linc00473 Promotes Tumor Growth and Alters Mitochondrial Fitness In Fibrolamellar Carcinoma).
- Abstract
New research from Cornell University explores fibrolamellar carcinoma (FLC), a rare liver cancer that primarily affects adolescents and young adults. The study focuses on the DNAJB1-PRKACA (DP fusion) oncogene, which is commonly found in FLC patients. The researchers identify a primate-specific long noncoding RNA called LINC00473 that is consistently elevated in FLC tumors. They demonstrate that LINC00473 promotes tumor growth and alters mitochondrial fitness, suggesting it could be a potential target for therapeutic intervention. The study sheds light on the mechanisms underlying FLC pathogenesis and highlights the need for new treatment options. [Extracted from the article]
- Published
- 2024
30. Early Experiences with Triple Immunochemotherapy in Adolescents and Young Adults with High-Risk Fibrolamellar Carcinoma.
- Author
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Gottlieb, Sara, O'Grady, Claire, Gliksberg, Ariel, and Kent, Paul
- Subjects
- *
THERAPEUTIC use of interferons , *ACQUISITION of data methodology , *CANCER chemotherapy , *TIME , *RETROSPECTIVE studies , *TREATMENT duration , *CANCER patients , *FLUOROURACIL , *MEDICAL records , *SURVIVAL analysis (Biometry) , *DESCRIPTIVE statistics , *HEPATOCELLULAR carcinoma , *IMMUNOTHERAPY - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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31. New insights into the pathophysiology and clinical care of rare primary liver cancersKey points
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Elia Gigante, Valérie Paradis, Maxime Ronot, François Cauchy, Olivier Soubrane, Nathalie Ganne-Carrié, and Jean-Charles Nault
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Mixed tumor ,Hepatocholangiocarcinoma ,Fibrolamellar carcinoma ,Hepatic hemangioendothelioma ,Hepatocellular carcinoma ,Hepatic angiosarcoma ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Summary: 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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- 2021
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32. Fibrolamellar Carcinoma With Predominantly Pseudoglandular Architecture: A Potential Diagnostic Pitfall.
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du Toit, Mariëtte and Aldera, Alessandro Pietro
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- *
CARCINOMA , *SURGICAL pathology , *LIVER biopsy , *INTRAHEPATIC bile ducts , *IMMUNOSTAINING , *HEPATOCELLULAR carcinoma - Abstract
Biopsies of liver mass lesions are encountered frequently in general surgical pathology practice. The clinical differential diagnosis is typically hepatocellular carcinoma (HCC) versus metastatic adenocarcinoma. There are a variety of HCC variants that show a range of morphological appearances. The presence of malignant glands in the liver prompts the pathologist to consider adenocarcinoma, either metastatic or primary intrahepatic cholangiocarcinoma. It is important to remember that some variant patterns of HCC can show pseudoglandular growth. In this article, we present a case of fibrolamellar carcinoma that showed predominantly pseudoglandular growth to highlight the importance of a systematic approach and the routine use of a panel of immunohistochemical stains (HepPar1, CK7, and CD68). [ABSTRACT FROM AUTHOR]
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- 2021
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33. DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma.
- Author
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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 Jr, 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, and Thomas PG
- Subjects
- Humans, Receptors, Antigen, T-Cell genetics, T-Lymphocytes pathology, Cell- and Tissue-Based Therapy, HSP40 Heat-Shock Proteins genetics, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits genetics, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular therapy, Carcinoma, Hepatocellular pathology
- 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., Competing Interests: Declaration of interests J.C.C., A.M.K., A.E.Z., S.E.S., and P.G.T. have a patent application for TCRs for treating FLC. J.C.C. has additional patent applications in the field of immunotherapy. A.W.P. is a member of the scientific advisory board (SAB) of Bioinformatics Solutions Inc. (Canada), shareholder and SAB member of Evaxion Biotech (Denmark), consultant for Grey Wolf Therapeutics (UK), and cofounder of Resseptor Therapeutics (Melbourne). S.G. is a co-inventor on patent applications in the fields of cell/gene therapy for cancer, consultant of TESSA Therapeutics, member of the Data and Safety Monitoring Board of Immatics, and SAB member of Be Biopharma and has received honoraria from Tidal, Catamaran Bio, and Sanofi within the last 2 years. S.E.S. is a cofounder, stockholder, and paid consultant for Gliknik Inc., serves on the SAB and holds stock options for Virion Inc., and receives royalties from the Mayo Clinic for licensed IP surrounding manipulation of the PD-1:PD-L1 pathway for cancer treatment. P.G.T. is on the SAB of Immunoscape and Shennon Bio, received personal fees and research support from Elevate Bio, and consulted for 10×, Illumina, Pfizer, Cytoagents, and JNJ., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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34. Bilateral Adnexal Masses in a Young Female: Rare Presentation of Hepatocellular Carcinoma With Review of the Literature.
- Author
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Gargi, Kapatia, Parikshaa, Gupta, Saha, Pradip K., Rohit, Mehtani, Madhumita, Premkumar, and Rajvanshi, Arvind
- Subjects
- *
HEPATOCELLULAR carcinoma , *ADNEXAL diseases , *METASTASIS , *IMMUNOHISTOCHEMISTRY , *OVARIES - Abstract
Ovaries are a common niche for metastasis. Metastatic malignancies account for 5–30% of all ovarian malignancies. Hepatocellular carcinoma (HCC) is one of the rare malignancies to metastasize to the ovaries. Of all the variants of HCC, fibrolamellar HCC (FLHCC) variant is extremely uncommon and accounts for around 1% of all HCC cases. FLHCC metastasizing to ovaries, at presentation, is an exceptional occurrence. We present a case of a young female who presented with bilateral adnexal masses and was diagnosed as metastatic FLHCC on histopathological examination and confirmed by immunohistochemistry. In addition, a thorough literature review highlighting the previously reported cases is also presented. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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35. DnaJ-PKAc fusion induces liver inflammation in a zebrafish model of fibrolamellar carcinoma
- Author
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Sofia de Oliveira, Ruth A. Houseright, Benjamin G. Korte, and Anna Huttenlocher
- Subjects
fibrolamellar carcinoma ,liver ,inflammation ,early progression ,non-invasive imaging ,Medicine ,Pathology ,RB1-214 - Abstract
Fibrolamellar carcinoma (FLC) is a rare liver cancer that affects adolescents and young adults. Genomic analysis of FLC has revealed a 400 kb deletion in chromosome 19 that leads to the chimeric transcript DNAJB1-PRKACA (DnaJ-PKAc), comprised of the first exon of heat shock protein 40 (DNAJB1) and exons 2-10 of the catalytic subunit of protein kinase A (PRKACA). Here, we report a new zebrafish model of FLC induced by ectopic expression of zebrafish Dnaja-Pkaca (zfDnaJa-Pkaca) in hepatocytes that is amenable to live imaging of early innate immune inflammation. Expression of zfDnaJa-Pkaca in hepatocytes induces hepatomegaly and increased hepatocyte size. In addition, FLC larvae exhibit early innate immune inflammation characterized by early infiltration of neutrophils and macrophages into the liver microenvironment. Increased Caspase-a (the zebrafish homolog for human caspase-1) activity was also found in the liver of FLC larvae, and pharmacological inhibition of Tnfα and caspase-a decreased liver size and inflammation. Overall, these findings show that innate immune inflammation is an early feature in a zebrafish model of FLC and that pharmacological inhibition of TNFα or caspase-1 activity might be targets to treat inflammation and progression in FLC patients. This article has an associated First Person interview with the first author of the paper.
- Published
- 2020
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36. Researchers from University of Washington School of Medicine Publish New Studies and Findings in the Area of Fibrolamellar Carcinoma (Reversing immunosuppression in the tumor microenvironment of fibrolamellar carcinoma via PD-1 and IL-10...).
- Abstract
A new study conducted by researchers from the University of Washington School of Medicine explores the immune response to fibrolamellar carcinoma (FLC), a rare liver tumor. The study found that immune cells are concentrated in fibrous stromal bands rather than in the carcinoma cell compartment. T cells in FLC demonstrated decreased activation and regulatory T cells had more frequent expression of PD-1 and CTLA-4 compared to non-tumor liver cells. The researchers concluded that combination immunotherapy targeting PD-1 and IL-10 could potentially reverse the immunosuppression in the FLC tumor microenvironment. [Extracted from the article]
- Published
- 2024
37. Fibrolamellar carcinoma: Challenging the challenge.
- Author
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Lamarca, Angela, Frizziero, Melissa, Fulton, Alexander, McNamara, Mairéad G., Filobbos, Rafik, Hubner, Richard A., Wardell, Steve, and Valle, Juan W.
- Subjects
- *
ANTINEOPLASTIC agents , *THERAPEUTIC use of interferons , *CANCER chemotherapy , *FLUOROURACIL , *HEALTH services accessibility , *INTERFERONS , *LIVER tumors , *TREATMENT effectiveness - Abstract
Fibrolamellar carcinoma (FLC) is a rare and poorly understood malignancy, which seems to be more prevalent in young patients compared with conventional hepatocellular carcinoma (HCC). Performing prospective clinical trials recruiting patients diagnosed with FLC has proven challenging with scarce data available guiding clinical management. The use of a number of chemotherapy compounds in these patients, including cisplatin, epirubicin, 5-fluorouracil (5-FU) and recombinant interferon α-2B (IFN-α-2B), has been reported in the literature, mainly in the form of case reports. The most promising systemic therapy tested so far is the combination of 5-FU infusion and 3-weekly IFN-α-2B, based on results from a phase II clinical trial. This article provides an overview of our own experience with this treatment schedule for patients with FLC, confirming its activity and treatment-derived benefit in the real world. Current challenges being faced by healthcare professionals treating patients with advanced FLC are discussed, especially the increasingly limited access to IFN-α-2B, which could compromise the access to an active therapy in the coming future, and the difficulties in the development of new treatment options for advanced FLC. • Fibrolamellar carcinoma is a liver cancer. • Evidence supporting systemic therapy is scarce. • Most promising systemic therapy is based on 5-fluorouracil infusion and interferon α-2B (IFN-α-2B). • There is an increasingly limited access to IFN-α-2B. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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38. Fibrolamellar hepatocellular carcinoma: Case report.
- Author
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Shtefanov, Ivan I., Akhmedin, Darkhan N., Kukanova, Assiya M., Zhakipova, Ainagul A., and Makishev, Abai K.
- Subjects
- *
FIBROLAMELLAR hepatocellular carcinoma , *LIVER cancer , *TUMOR classification - Abstract
Introduction: Fibrolamellar carcinoma is a rare primary hepatic malignant tumour, which was first described as a pathological variant of hepatocellular carcinoma. Aim: The aim of the paper is to discuss the case report of surgical treatment of a multicentric form of presumably fibrolamellar carcinoma significantly exceeding the Barcelona Clinic Liver Cancer staging system criteria, although tumour size and multi-organ lesions are not a contraindication to resection. Case study: This case report is an original one because the surgical intervention was performed on a patient with a multicentric fibrolamellar hepatocellular carcinoma with the initial foci of 16.0 × 12.0 × 9.0 cm and 10.5 × 8.7 × 7.5 cm. Results and discussion: The surgical intervention (right hemihepatectomy, lymphatic dissection D2) was performed as an independent treatment without prior chemotherapy. Conclusions: The surgical treatment occurred 5 years ago, and at the time of writing there has been no relapse and no sign of progression. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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39. BAP1 mutations define a homogeneous subgroup of hepatocellular carcinoma with fibrolamellar-like features and activated PKA.
- Author
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Hirsch, Théo Z., Negulescu, Ana, Gupta, Barkha, Caruso, Stefano, Noblet, Bénédicte, Couchy, Gabrielle, Bayard, Quentin, Meunier, Léa, Morcrette, Guillaume, Scoazec, Jean-Yves, Blanc, Jean-Frédéric, Amaddeo, Giuliana, Nault, Jean-Charles, Bioulac-Sage, Paulette, Ziol, Marianne, Beaufrère, Aurélie, Paradis, Valérie, Calderaro, Julien, Imbeaud, Sandrine, and Zucman-Rossi, Jessica
- Subjects
- *
HEPATOCELLULAR carcinoma , *LIVER tumors , *LIVER cancer , *CIRRHOSIS of the liver , *YOUNG adults - Abstract
DNAJB1 - PRKACA fusion is a specific driver event in fibrolamellar carcinoma (FLC), a rare subtype of hepatocellular carcinoma (HCC) that occurs in adolescents and young adults. In older patients, molecular determinants of HCC with mixed histological features of HCC and FLC (mixed-FLC/HCC) remain to be discovered. A series of 151 liver tumors including 126 HCC, 15 FLC, and 10 mixed-FLC/HCC were analyzed by RNAseq and whole-genome- or whole-exome sequencing. Western blots were performed to validate genomic discoveries. Results were validated using the TCGA database. Most of the mixed-FLC/HCC RNAseq clustered in a robust subgroup of 17 tumors, which all had mutations or translocations inactivating BAP1 , the gene encoding BRCA1-associated protein-1. Like FLC, BAP1-HCC were significantly enriched in females, patients with a lack of chronic liver disease, and fibrotic tumors compared to non-BAP1 HCC. However, patients were older and had a poorer prognosis than those with FLC. BAP1 tumors were immune hot, showed progenitor features and did not show DNAJB1 - PRKACA fusion, while almost none of these tumors had mutations in CTNNB1 , TP53 and TERT promoter. In contrast, 80% of the BAP1 tumors showed a chromosome gain of PRKACA at 19p13, combined with a loss of PRKAR2A (coding for the inhibitory regulatory subunit of PKA) at 3p21, leading to a high PRKACA/PRKAR2A ratio at the mRNA and protein levels. We have characterized a subgroup of BAP1 -driven HCC with fibrolamellar-like features and a dysregulation of the PKA pathway, which could be at the root of the clinical and histological similarities between BAP1 tumors and DNAJB1 - PRKACA FLCs. Herein, we have defined a homogeneous subgroup of hepatocellular carcinomas in which the BAP1 gene is inactivated. This leads to the development of cancers with features similar to those of fibrolamellar carcinoma. These tumors more frequently develop in females without chronic liver disease or cirrhosis. The presence of PKA activation and T cell infiltrates suggest that these tumors could be treated with PKA inhibitors or immunomodulators. • BAP1 -inactivating alterations define a homogeneous subgroup of HCC characterized by fibrolamellar-like features. • These tumors frequently develop in females, with non-cirrhotic livers. • Patients with BAP1-inactivated HCC could benefit from drugs inactivating PKA and immunomodulators. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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40. Estudio imagenológico de tumor maligno en el hígado.
- Author
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Chang Cañarte, Diana Lisbeth, Castro Gómez, Tatiana Elizabeth, Córdova Garcia, Genesis Lisette, and Morrillo Camacho, Daniel Gregorio
- Subjects
CIRRHOSIS of the liver ,SERVER farms (Computer network management) ,NUCLEAR magnetic resonance ,RARE diseases ,YOUNG adults ,LIVER diseases - Abstract
Copyright of Dilemas Contemporáneos: Educación, Política y Valores is the property of Dilemas Contemporaneos: Educacion, Politica y Valores and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2020
41. Neoplasms of the Liver and Biliary System
- Author
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Nakanishi, Yukihiro, Saxena, Romil, Cheng, Liang, editor, and Bostwick, David G., editor
- Published
- 2016
- Full Text
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42. An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma
- Author
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Rigney E Turnham, F Donelson Smith, Heidi L Kenerson, Mitchell H Omar, Martin Golkowski, Irvin Garcia, Renay Bauer, Ho-Tak Lau, Kevin M Sullivan, Lorene K Langeberg, Shao-En Ong, Kimberly J Riehle, Raymond S Yeung, and John D Scott
- Subjects
Protein kinase A ,combination therapy ,fibrolamellar carcinoma ,MAP kinase ,intratumoral heterogeneity ,local signaling ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Fibrolamellar carcinoma (FLC) is a rare liver cancer. FLCs uniquely produce DNAJ-PKAc, a chimeric enzyme consisting of a chaperonin-binding domain fused to the Cα subunit of protein kinase A. Biochemical analyses of clinical samples reveal that a unique property of this fusion enzyme is the ability to recruit heat shock protein 70 (Hsp70). This cellular chaperonin is frequently up-regulated in cancers. Gene-editing of mouse hepatocytes generated disease-relevant AML12DNAJ-PKAc cell lines. Further analyses indicate that the proto-oncogene A-kinase anchoring protein-Lbc is up-regulated in FLC and functions to cluster DNAJ-PKAc/Hsp70 sub-complexes with a RAF-MEK-ERK kinase module. Drug screening reveals Hsp70 and MEK inhibitor combinations that selectively block proliferation of AML12DNAJ-PKAc cells. Phosphoproteomic profiling demonstrates that DNAJ-PKAc biases the signaling landscape toward ERK activation and engages downstream kinase cascades. Thus, the oncogenic action of DNAJ-PKAc involves an acquired scaffolding function that permits recruitment of Hsp70 and mobilization of local ERK signaling.
- Published
- 2019
- Full Text
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43. Diagnostic approach to well-differentiated hepatocellular carcinoma
- Author
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Michael Torbenson
- Subjects
Pathology ,medicine.medical_specialty ,Histology ,Adenoma ,business.industry ,Focal nodular hyperplasia ,Hepatocellular adenoma ,medicine.disease ,Glypican 3 ,digestive system diseases ,Pathology and Forensic Medicine ,stomatognathic diseases ,Hepatocellular carcinoma ,Medicine ,Differential diagnosis ,business ,Fibrolamellar Carcinoma ,Well Differentiated Hepatocellular Carcinoma - Abstract
Well-differentiated hepatocellular mass-lesions in non-cirrhotic livers have a differential diagnosis of focal nodular hyperplasia, regenerative hepatic pseudotumors, hepatic adenoma, hepatocellular carcinoma, and fibrolamellar carcinoma. Despite significant advances in characterizing these pseudotumors and tumors, they remain a diagnostic challenge, especially on needle biopsy. This review focuses on a systematic diagnostic approach, one that allows confident diagnosis of these lesions.
- Published
- 2022
44. Neoplasms of the Liver and Biliary System
- Author
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Saxena, Romil, Cheng, Liang, editor, and Bostwick, David G., editor
- Published
- 2011
- Full Text
- View/download PDF
45. Hepatocellular Carcinoma
- Author
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Bartolozzi, Carlo, Franchini, Chiara, and Baert, Albert L., editor
- Published
- 2008
- Full Text
- View/download PDF
46. Identification of Novel Therapeutic Targets for Fibrolamellar Carcinoma Using Patient-Derived Xenografts and Direct-from-Patient Screening
- Author
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Ethan M. Weinberg, Michael Torbenson, Nicole J.C. Narayan, William J. Hammond, Gadi Lalazar, Ruisi Wang, Solomon Levin, Denise Ng, Michael P. LaQuaglia, Lavoisier Ramos-Espiritu, David Requena, J. Fraser Glickman, Barbara A. Lyons, Rory L. Smoot, Charles M. Rice, Eleftherios Michailidis, Jessica Ellison, Benjamin A. Farber, Erik Schadde, Hans-Guido Wendel, Koen Vercauteren, Faith Tierney, Arlene Hurley, Patrick Bhola, Mark J. Truty, Tomoaki Kato, Martin Hertl, Philip Coffino, Mohammad Kabbani, Anthony Letai, Jennifer L. Leiting, Ype P. de Jong, Bassem Shebl, Sanford M. Simon, James A. Saltsman, and Michael V. Ortiz
- Subjects
Male ,Drug ,Carcinoma, Hepatocellular ,media_common.quotation_subject ,Patient screening ,Antineoplastic Agents ,Article ,Mice ,medicine ,Animals ,Humans ,Benzofurans ,media_common ,Sulfonamides ,Aniline Compounds ,business.industry ,Liver Neoplasms ,Cancer ,medicine.disease ,Precision medicine ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,On cells ,Oncology ,Antiapoptotic protein ,eIF4A ,Cancer research ,Female ,business ,Fibrolamellar Carcinoma ,Naphthoquinones - Abstract
To repurpose therapeutics for fibrolamellar carcinoma (FLC), we developed and validated patient-derived xenografts (PDX) from surgical resections. Most agents used clinically and inhibitors of oncogenes overexpressed in FLC showed little efficacy on PDX. A high-throughput functional drug screen found primary and metastatic FLC were vulnerable to clinically available inhibitors of TOPO1 and HDAC and to napabucasin. Napabucasin's efficacy was mediated through reactive oxygen species and inhibition of translation initiation, and specific inhibition of eIF4A was effective. The sensitivity of each PDX line inversely correlated with expression of the antiapoptotic protein Bcl-xL, and inhibition of Bcl-xL synergized with other drugs. Screening directly on cells dissociated from patient resections validated these results. This demonstrates that a direct functional screen on patient tumors provides therapeutically informative data within a clinically useful time frame. Identifying these novel therapeutic targets and combination therapies is an urgent need, as effective therapeutics for FLC are currently unavailable. Significance: Therapeutics informed by genomics have not yielded effective therapies for FLC. A functional screen identified TOPO1, HDAC inhibitors, and napabucasin as efficacious and synergistic with inhibition of Bcl-xL. Validation on cells dissociated directly from patient tumors demonstrates the ability for functional precision medicine in a solid tumor. This article is highlighted in the In This Issue feature, p. 2355
- Published
- 2021
47. Chonnam National University Researcher Provides New Data on Fibrolamellar Carcinoma (Identification of Long Non-Coding RNA Profiles and Potential Therapeutic Agents for Fibrolamellar Carcinoma Based on RNA-Sequencing Data).
- Subjects
LINCRNA ,CARCINOMA ,PROTEIN kinase C - Abstract
Keywords: Cancer; Carcinomas; Drugs and Therapies; Fibrolamellar Carcinoma; Genetics; Health and Medicine; Oncology EN Cancer Carcinomas Drugs and Therapies Fibrolamellar Carcinoma Genetics Health and Medicine Oncology 193 193 1 09/11/23 20230912 NES 230912 2023 SEP 11 (NewsRx) -- By a News Reporter-Staff News Editor at Clinical Oncology Week -- Researchers detail new data in fibrolamellar carcinoma. Cancer, Carcinomas, Drugs and Therapies, Fibrolamellar Carcinoma, Genetics, Health and Medicine, Oncology. [Extracted from the article]
- Published
- 2023
48. Recruitment of BAG2 to DNAJ-PKAc scaffolds promotes cell survival and resistance to drug-induced apoptosis in fibrolamellar carcinoma.
- Published
- 2023
49. The Role of Liver Transplantation in the Treatment of Primary Liver Tumors
- Author
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Neuhaus, Peter, Jonas, Sven, Kitajima, Masaki, editor, Shimazu, Motohide, editor, Wakabayashi, Go, editor, Hoshino, Ken, editor, Tanabe, Minoru, editor, and Kawachi, Shigeyuki, editor
- Published
- 2002
- Full Text
- View/download PDF
50. Pediatric Liver Tumors
- Author
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Soo-Jin Cho
- Subjects
Hepatoblastoma ,Pathology ,medicine.medical_specialty ,Liver tumor ,business.industry ,Not Otherwise Specified ,Context (language use) ,medicine.disease ,Malignancy ,digestive system diseases ,Pathology and Forensic Medicine ,Hepatocellular carcinoma ,medicine ,Neoplasm ,Surgery ,business ,Fibrolamellar Carcinoma - Abstract
Malignant primary liver tumors are rare in children. Yet a wide histologic spectrum is seen, particularly in hepatoblastoma, the most common malignant liver tumor in children. Furthermore, there can be significant morphologic overlap with hepatocellular carcinoma, the second most common pediatric liver malignancy, and tumors with hybrid features of hepatoblastoma and hepatocellular carcinoma are also reported (currently placed in the provisional category of malignant hepatocellular neoplasm, not otherwise specified). This review provides detailed morphologic descriptions and updates in the evolving clinical context of these tumors, and presents recent molecular advances that may further help in accurate classification of these tumors, which is critical in their management.
- Published
- 2020
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