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1
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Mehta PA, Nelson A, Loveless S, Lane A, Fukuda T, Teusink-Cross A, Elder D, Lagory D, Miller E, Cancelas JA, Howell J, Zhao J, Mizuno K, Myers KC, Lake K, McIntosh K, Setchell KDR, Luebbering N, Edwards S, Chihanga T, Wells SI, Davies SM. Phase 1 study of quercetin, a natural antioxidant for children and young adults with Fanconi anemia. Blood Adv 2025; 9:1927-1939. [PMID: 39820512 PMCID: PMC12008688 DOI: 10.1182/bloodadvances.2024015053] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 12/04/2024] [Accepted: 12/24/2024] [Indexed: 01/19/2025] Open
Abstract
ABSTRACT Fanconi anemia (FA) is a rare inherited disorder characterized by progressive bone marrow failure (BMF) and a predisposition to malignancy. Systemic reactive oxygen species (ROS) and increased sensitivity of FA hematopoietic progenitors to ROS play a key role in the pathogenesis of BMF. Treatment with antioxidants improve hematopoietic function in Fancc-/- mice. We report the safety, tolerability, and pharmacokinetics of quercetin, a naturally occurring antioxidant in the first dose-finding phase 1 study for patients with FA. Twelve patients (median age, 7 years [range, 3-21]) received oral quercetin twice daily for 4 months. Quercetin was well tolerated at all dose levels. Allometrically bodyweight-adjusted dose with a maximum adult daily dose of 4000 mg/d was established as the recommended dose of quercetin. Patients in an expansion cohort (n = 18) were treated using this recommended dose for 6 months. A subset of patients showed reduced ROS levels in the peripheral blood (PB) and bone marrow stem cell compartment. Patients in the analysis cohort treated with the recommended dose of quercetin achieved an a priori-defined optimal response of 25% reduction in the PB ROS level compared with baseline. Platelet counts remained stable to slightly improved over the study period (P = .06). Absolute neutrophil counts (P = .01) and hemoglobin levels gradually declined (P = .001). In those with evidence of BMF at baseline, 8 of 15 patients (53%) had a hematological response at some point after quercetin treatment. Fluctuations in counts are common in patients with FA, limiting accurate assessment of the impact of quercetin use in FA. This trial was registered at www.ClinicalTrials.gov as #NCT01720147.
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Affiliation(s)
- Parinda A. Mehta
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Adam Nelson
- Bone Marrow Transplant MDT, Kids Cancer Centre, Sydney Children's Hospital Randwick, Australia
| | - Sara Loveless
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Adam Lane
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Tsuyoshi Fukuda
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Translational and Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Ashley Teusink-Cross
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Deborah Elder
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Denise Lagory
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Clinical Pharmacology, Investigational Pharmacy, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Erica Miller
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Jose A. Cancelas
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Hoxworth Blood Center Academic Unit, University of Cincinnati College of Medicine, Cincinnati, OH
- Reilly and O’Connell Families Cell Manipulation Core Facility and Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Jonathan Howell
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Junfang Zhao
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Kana Mizuno
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Translational and Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Kasiani C. Myers
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Kelly Lake
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Kelly McIntosh
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Kenneth D. R. Setchell
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Nathan Luebbering
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Stephanie Edwards
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Tafadzwa Chihanga
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Susanne I. Wells
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Stella M. Davies
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
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2
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Zhao B, Zhou X, Zheng P, Zhang B, Feng X, Chen J, Cai L, Chen Y, He L, Su J, Cheng S, Zeng Y, Li G, Ji B, Wu J, Feng W, Liu M, Jin Y, Liu T, Mo X, Wu J, Wu H, Zhang H, Zheng Z, Zheng Z, Sun J, Li Y, Guangdong Pharmaceutical Association, Hematology Group of Rare Disease Expert Committee of Guangdong Pharmaceutical Association. Expert consensus on the off-label use in China of drugs for rare hematologic diseases (2024 edition). Front Pharmacol 2024; 15:1477550. [PMID: 39650164 PMCID: PMC11621627 DOI: 10.3389/fphar.2024.1477550] [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: 08/08/2024] [Accepted: 09/17/2024] [Indexed: 12/11/2024] Open
Abstract
Drug package inserts are a crucial foundation for clinical medication practices and serve as the legal basis for guiding rational drug use and ensuring patient safety and efficacy. As rare disease treatments evolve, current package inserts often need to meet the clinical requirements for treating such conditions, frequently resulting in off-label drug use. This consensus is derived from discussions between Guangdong Pharmaceutical Association Hematologic Rare Diseases Group experts. The consensus aims to provide a framework and reference for the clinical application of off-label drug use in treating rare hematologic diseases.
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Affiliation(s)
- Boxin Zhao
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xuan Zhou
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ping Zheng
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bo Zhang
- Department of Pharmacy, Peking Union Medical College Hospital, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
| | - Xiaoqin Feng
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jie Chen
- Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Lisheng Cai
- Department of Hematology, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Yilu Chen
- Department of Pharmacy, Guangzhou Women and Children’s Medical Center, Guangzhou, China
| | - Liya He
- Department of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou, China
| | - Jianfen Su
- Department of Pharmacy, Panyu Central Hospital, Guangzhou, China
| | - Shuqin Cheng
- Department of Hematology, Panyu Central Hospital, Guangzhou, China
| | - Yingtong Zeng
- Department of Pharmacy, Guangdong Provincial People’s Hospital, Southern Medical University, Guangzhou, China
| | - Guowei Li
- Department of Hematology, Huizhou Central People’s Hospital, Huizhou, China
| | - Bo Ji
- Department of Clinical Pharmacy, General Hospital of Southern Theatre Command of PLA, Guangzhou, China
| | - Jianlong Wu
- Department of Pharmacy, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Weiyi Feng
- Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Maobai Liu
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, China
| | - Yiran Jin
- Department of Pharmacy, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Taotao Liu
- Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiaolan Mo
- Department of Pharmacy, Guangzhou Women and Children’s Medical Center, Guangzhou, China
| | - Junyan Wu
- Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Hui Wu
- Department of Pharmacy, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Hongliang Zhang
- Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhichang Zheng
- Department of Pharmacy, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Zhihua Zheng
- Guangdong Pharmaceutical Association, Guangzhou, China
| | - Jing Sun
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yilei Li
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Hoover A, Turcotte LM, Phelan R, Barbus C, Rayannavar A, Miller BS, Reardon EE, Theis-Mahon N, MacMillan ML. Longitudinal clinical manifestations of Fanconi anemia: A systematized review. Blood Rev 2024; 68:101225. [PMID: 39107201 PMCID: PMC11568946 DOI: 10.1016/j.blre.2024.101225] [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: 06/05/2024] [Revised: 07/29/2024] [Accepted: 07/29/2024] [Indexed: 08/09/2024]
Abstract
Fanconi anemia (FA) is a rare and complex inherited genetic disorder characterized by impaired DNA repair mechanisms leading to genomic instability. Individuals with FA have increased susceptibility to congenital anomalies, progressive bone marrow failure, leukemia and malignant tumors, endocrinopathies and other medical issues. In recent decades, steadily improved approaches to hematopoietic cell transplantation (HCT), the only proven curative therapy for the hematologic manifestations of FA, have significantly increased the life expectancy of affected individuals, illuminating the need to understand the long-term consequences and multi-organ ramifications. Utilizing a systematized review approach with narrative synthesis of each primary issue and organ system, we shed light on the challenges and opportunities for optimizing the care and quality of life for individuals with FA and identify knowledge gaps informing future research directions.
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Affiliation(s)
- Alex Hoover
- Division of Blood and Marrow Transplantation & Cellular Therapy, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
| | - Lucie M Turcotte
- Division of Hematology and Oncology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
| | - Rachel Phelan
- Division of Hematology, Oncology, and Blood and Marrow Transplant, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Crystal Barbus
- Division of Endocrinology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
| | - Arpana Rayannavar
- Division of Endocrinology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
| | - Bradley S Miller
- Division of Endocrinology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
| | - Erin E Reardon
- Woodruff Health Sciences Center Library, Emory University, Atlanta, GA, USA
| | | | - Margaret L MacMillan
- Division of Blood and Marrow Transplantation & Cellular Therapy, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
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He Y, Xu ZL, Ma R, Liu J, Zhang YY, Lyu M, Mo XD, Yan CH, Sun YQ, Zhang XY, Wang Y, Zhang XH, Huang XJ, Xu LP. [Prognostic analysis of 8 patients with hepatic adenoma undergoing allogeneic hematopoietic stem cell transplantation]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2024; 45:816-820. [PMID: 39414603 PMCID: PMC11518903 DOI: 10.3760/cma.j.cn121090-20240329-00120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Indexed: 10/18/2024]
Abstract
Objective: To evaluate the safety of patients with hepatic adenoma undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: A retrospective analysis of the clinical characteristics and prognosis of eight patients with hepatic adenoma who underwent allo-HSCT in the Hematology Department of Peking University People's Hospital from January 2010 to March 2024 was conducted. Results: Of the eight patients who underwent allo-HSCT with hepatic adenoma, one patient was considered MDS-h transfusion-dependent and seven had aplastic anemia. The median age of the patients was 23 years (13-48 years). The median time from the diagnosis of AA or MDS to transplantation was 14 years (6-24 years), whereas the median time from taking androgens to diagnosing hepatic adenoma was 9 years (5-13 years). Six cases underwent haplo-HSCT, one case underwent matched unrelated donor HSCT, and one case underwent matched related donor HSCT. All patients achieved neutrophil engraftment at a median time of 11.5 days (11-20 days) and PLT engraftment within 60 days at a median of 19 days (10-37 days) after haplo-HSCT. Moreover, seven patients developed CMV anemia after transplantation, three patients had hemorrhagic cystitis, and two patients developed acute GVHD. During and after transplantation, eight patients did not show severe liver function damage or rupture of hepatic adenoma. In relation to imaging size, four patients showed varying degrees of reduction in hepatic adenoma size after transplantation, whereas four patients did not show significant changes in hepatic adenoma size after transplantation. The median follow-up time was 540.5 (30-2 989) days. Of the eight patients, six survived and two died. Furthermore, no direct correlation was observed between death and hepatic adenoma. Conclusion: Patients with hepatic adenomas undergoing allo-HSCT are not contraindications for transplantation, which will not increase transplant-related mortality.
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Affiliation(s)
- Y He
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - Z L Xu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - R Ma
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - J Liu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - Y Y Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - M Lyu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - X D Mo
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - C H Yan
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - Y Q Sun
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - X Y Zhang
- Peking University People's Hospital Department of Medical imaging, Beijing 100044, China
| | - Y Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - X H Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - X J Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
| | - L P Xu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
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Tóth M, Kirchner M, Longerich T, Stenzinger A, Schirmacher P. Integrated genotype-phenotype analysis of familial adenomatous polyposis-associated hepatocellular adenomas. Virchows Arch 2024; 484:587-595. [PMID: 37872280 PMCID: PMC11062996 DOI: 10.1007/s00428-023-03680-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 09/25/2023] [Accepted: 10/10/2023] [Indexed: 10/25/2023]
Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by a germline mutation in the adenomatous polyposis coli (APC) gene, characterized by numerous colorectal adenomas. In addition, FAP patients may develop extraintestinal manifestations. Several cases of hepatocellular adenomas (HCA) detected accidentally in FAP patients have raised the so-far unsolved question of whether they represent a specific manifestation of FAP or a mere coincidence. To investigate the incidence of liver tumors in FAP patients, we analyzed our diagnostic database from 1991 to 2021. Among the 58 hepatic mass lesions identified, five HCAs occurring in three patients with FAP were identified, and comprehensive morphological, immunohistological, and molecular analysis employing targeted next-generation sequencing was conducted for characterization. The HCAs in this study showed no cytological or histological atypia. They displayed a diffuse, strong positivity for glutamine synthetase but no nuclear beta-catenin immunostaining. In two patients, the adenomas showed moderate immunoreactivity against serum amyloid A. Consistent with the diagnosis of FAP, molecular profiling revealed a pathogenic germline mutation of the APC gene in all analyzed adenomas as well as deleterious somatic second hits. All somatic mutations were localized between codons 1345 and 1577. No mutations were found in the catenin beta 1 gene. HCA in FAP patients can be a specific, although rare, neoplastic manifestation of this inborn disease and represents a distinct subgroup of HCAs. These benign tumors represent an important differential diagnosis for hepatic metastases in FAP patients and require adequate clinical and molecular (diagnostic) assessments for optimal patient guidance.
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Affiliation(s)
- Marcell Tóth
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
| | - Martina Kirchner
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Thomas Longerich
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Albrecht Stenzinger
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
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Snyder AJ, Campbell KM, Lane A, Mehta PA, Myers K, Davies SM, Koo J. Liver abnormalities are frequent and persistent in patients with Fanconi anemia. Blood Adv 2024; 8:1427-1438. [PMID: 38231120 PMCID: PMC10955649 DOI: 10.1182/bloodadvances.2023012215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 01/02/2024] [Accepted: 01/07/2024] [Indexed: 01/18/2024] Open
Abstract
ABSTRACT Liver disease has not been well described in patients with Fanconi anemia (FA). Improvements in outcomes of transplant mean that more individuals with FA are reaching adulthood and new features of the FA phenotype are being discovered. We performed a retrospective review of liver function in a cohort of 97 patients with FA followed-up for at least 10 years at a single center. We identified a high frequency of transaminitis (n = 31, 32%) without elevation of bilirubin and with no evidence of structural hepatic abnormality in patients with FA. Transaminitis was persistent in many cases, sometimes lasting more than a decade without clinical manifestation, although 2 patients with prolonged transaminitis are deceased from liver failure, indicating important long-term clinical consequences. Transaminitis was found in patients who had and had not received transplant but was more frequent in recipients of transplant. Exposure to total body irradiation increased risk (odds ratio, 15.5 [95% confidence interval, 2.44-304.54]; P = .01), whereas treatment with androgens did not. Review of limited numbers of liver biopsies and autopsy material showed a cholestatic pattern of liver injury, with progressive fibrosis, in the majority of patients. Occurrence in cases without transplant as well as cases with transplant argues against a potential diagnosis of atypical liver graft-versus-host disease. Limited data regarding therapy suggest no benefit from treatment with steroids or other immune suppressive medications or ursodeoxycholic acid. Our data show that liver disease is common in patients with FA, and because most children with FA now reach adulthood, end-stage liver disease in young adulthood means systematic testing of potential therapies is urgently needed.
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Affiliation(s)
- Alana J. Snyder
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Kathleen M. Campbell
- Department of Pediatrics, University of Cincinnati, Cincinnati, OH
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Adam Lane
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati, Cincinnati, OH
| | - Parinda A. Mehta
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati, Cincinnati, OH
| | - Kasiani Myers
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati, Cincinnati, OH
| | - Stella M. Davies
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati, Cincinnati, OH
| | - Jane Koo
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati, Cincinnati, OH
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7
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Jambi S, Mirza A, Zughaibi T, Khalil H, Borai A. The assessment of liver function test and fertility hormones in Saudi athletes using anabolic androgenic steroids. Saudi Pharm J 2024; 32:101954. [PMID: 38292405 PMCID: PMC10825542 DOI: 10.1016/j.jsps.2024.101954] [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: 07/26/2023] [Accepted: 01/08/2024] [Indexed: 02/01/2024] Open
Abstract
Background A growing number of athletes are using synthetic anabolic-androgenic steroids (AAS), comprised of testosterone and other derivatives, to enhance athletic performance and muscle mass. Over the years, numerous reports elucidated the side effects of the illegal use of AAS, such as infertility, and liver disorders. The effect of AAS on the hepatic and reproductive systems in Saudi athletes has not yet been studied. Therefore, this study examined the liver function and sex hormone parameters of AAS users as compared to non-users. Methods Fasting blood samples were collected from 16 male Saudi athletes, 10 AAS-users (cases) and 6 non-users (controls) to measure liver function tests (ALT, AST, GGT, ALP, total protein, albumin, direct and total bilirubin) and muscle enzymes (CK, LDH), Fertility hormones (LH, FSH, total testosterone, estradiol, and prolactin) were included also. Furthermore, a self-reported questionnaire was obtained to identify the type of AAS used, the dosage, and the length of the course before sample collection. Results The results show a statistically significant increase in ALT (P < 0.001), AST (P < 0.001), CK (P < 0.05), and a significant decrease (P < 0.05) in albumin (P < 0.001) and total bilirubin levels (P < 0.01) in AAS-users. Total testosterone increased significantly among AAS (P < 0.05), along with a significant decrease in LH (P < 0.01), and FSH (P < 0.001) levels, while serum prolactin and estradiol levels were significantly increased (P < 0.05). Conclusion AAS can enhance physical performance and appearance, its potential adverse effects on the hepatic and reproductive systems necessitate careful consideration. Our research demonstrates an increase in the liver-specific enzyme ALT in AAS users relative to non-users and the possibility that short-term AAS usage increases the risk of liver injury.
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Affiliation(s)
- Shatha Jambi
- King Abdullah International Medical Center, King Saud bin Abdul Aziz University for health science, Pathology, King Abdul-Aziz Medical City, Saudi Arabia
- King Saud bin Abdulaziz University for Health Sciences, Applied medical Sciences, Jeddah, Saudi Arabia
| | - Ahmed Mirza
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Science, King Abdul-Aziz University, Jeddah, Saudi Arabia
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Torki Zughaibi
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Science, King Abdul-Aziz University, Jeddah, Saudi Arabia
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Haitham Khalil
- King Abdullah International Medical Center, King Saud bin Abdul Aziz University for health science, Pathology, King Abdul-Aziz Medical City, Saudi Arabia
| | - Anwar Borai
- King Abdullah International Medical Center, King Saud bin Abdul Aziz University for health science, Pathology, King Abdul-Aziz Medical City, Saudi Arabia
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8
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-Like Lesions. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:842-946. [DOI: 10.1016/b978-0-7020-8228-3.00013-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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9
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Vissers LTW, van der Burg M, Lankester AC, Smiers FJW, Bartels M, Mohseny AB. Pediatric Bone Marrow Failure: A Broad Landscape in Need of Personalized Management. J Clin Med 2023; 12:7185. [PMID: 38002797 PMCID: PMC10672506 DOI: 10.3390/jcm12227185] [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: 10/26/2023] [Revised: 11/10/2023] [Accepted: 11/16/2023] [Indexed: 11/26/2023] Open
Abstract
Irreversible severe bone marrow failure (BMF) is a life-threatening condition in pediatric patients. Most important causes are inherited bone marrow failure syndromes (IBMFSs) and (pre)malignant diseases, such as myelodysplastic syndrome (MDS) and (idiopathic) aplastic anemia (AA). Timely treatment is essential to prevent infections and bleeding complications and increase overall survival (OS). Allogeneic hematopoietic stem cell transplantation (HSCT) provides a cure for most types of BMF but cannot restore non-hematological defects. When using a matched sibling donor (MSD) or a matched unrelated donor (MUD), the OS after HSCT ranges between 60 and 90%. Due to the introduction of post-transplantation cyclophosphamide (PT-Cy) to prevent graft versus host disease (GVHD), alternative donor HSCT can reach similar survival rates. Although HSCT can restore ineffective hematopoiesis, it is not always used as a first-line therapy due to the severe risks associated with HSCT. Therefore, depending on the underlying cause, other treatment options might be preferred. Finally, for IBMFSs with an identified genetic etiology, gene therapy might provide a novel treatment strategy as it could bypass certain limitations of HSCT. However, gene therapy for most IBMFSs is still in its infancy. This review summarizes current clinical practices for pediatric BMF, including HSCT as well as other disease-specific treatment options.
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Affiliation(s)
- Lotte T. W. Vissers
- Laboratory for Pediatric Immunology, Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (L.T.W.V.); (M.v.d.B.)
| | - Mirjam van der Burg
- Laboratory for Pediatric Immunology, Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (L.T.W.V.); (M.v.d.B.)
| | - Arjan C. Lankester
- Department of Pediatrics, Hematology and Stem Cell Transplantation, Willem-Alexander Children’s Hospital, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (A.C.L.); (F.J.W.S.)
| | - Frans J. W. Smiers
- Department of Pediatrics, Hematology and Stem Cell Transplantation, Willem-Alexander Children’s Hospital, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (A.C.L.); (F.J.W.S.)
| | - Marije Bartels
- Department of Pediatric Hematology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands;
| | - Alexander B. Mohseny
- Department of Pediatrics, Hematology and Stem Cell Transplantation, Willem-Alexander Children’s Hospital, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (A.C.L.); (F.J.W.S.)
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10
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Pothuri VS, Anzelmo M, Gallaher E, Ogunlana Y, Aliabadi-Wahle S, Tan B, Crippin JS, Hammill CW. Transgender Males on Gender-Affirming Hormone Therapy and Hepatobiliary Neoplasms: A Systematic Review. Endocr Pract 2023; 29:822-829. [PMID: 37286102 DOI: 10.1016/j.eprac.2023.05.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/21/2023] [Accepted: 05/29/2023] [Indexed: 06/09/2023]
Abstract
OBJECTIVE Behavioral therapy, gender-affirming hormone therapy (GAHT), and surgery are all components of a successful gender transition, but due to a historical lack of access, there is paucity of long-term data in this population. We sought to better characterize the risk of hepatobiliary neoplasms in transgender males undergoing GAHT with testosterone. METHODS In addition to the 2 case reports, a systematic literature review of hepatobiliary neoplasms in the setting of testosterone administration or endogenous overproduction across indications was conducted. The medical librarian created search strategies using keywords and controlled vocabulary in Ovid Medline, Embase.com, Scopus, Cochrane Database of Systematic Reviews, and clinicaltrials.gov. A total of 1273 unique citations were included in the project library. All unique abstracts were reviewed, and abstracts were selected for complete review. Inclusion criteria were articles reporting cases of hepatobiliary neoplasm development in patients with exogenous testosterone administration or endogenous overproduction. Non-English language articles were excluded. Cases were collated into tables based on indication. RESULTS Forty-nine papers had cases of hepatocellular adenoma, hepatocellular carcinoma, cholangiocarcinoma, or other biliary neoplasm in the setting of testosterone administration or endogenous overproduction. These 49 papers yielded 62 unique cases. CONCLUSION Results of this review are not sufficient to conclude that there is an association between GAHT and hepatobiliary neoplasms. This supports current evaluation and screening guidelines for initiation and continuation of GAHT in transgender men. The heterogeneity of testosterone formulations limits the translation of risks of hepatobiliary neoplasms in other indications to GAHT.
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Affiliation(s)
| | | | - Emily Gallaher
- Washington University School of Medicine, St. Louis, Missouri
| | | | | | - Benjamin Tan
- Washington University School of Medicine, St. Louis, Missouri; Department of Medicine, Washington University in St Louis, St Louis, Missouri; Alvin J. Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri
| | - Jeffrey S Crippin
- Washington University School of Medicine, St. Louis, Missouri; Department of Medicine, Washington University in St Louis, St Louis, Missouri
| | - Chet W Hammill
- Washington University School of Medicine, St. Louis, Missouri; Alvin J. Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri; Department of Surgery, Washington University in St Louis, St Louis, Missouri.
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11
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González IA, Torbenson M, Sharifai N, Byrnes K, Chatterjee D, Kakar S, Yeh MM, Wu TT, Zhang X, Jain D. Clinicopathologic characterization of hepatocellular adenomas in men: a multicenter experience. Hum Pathol 2023; 138:24-33. [PMID: 37245629 DOI: 10.1016/j.humpath.2023.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/18/2023] [Accepted: 05/22/2023] [Indexed: 05/30/2023]
Abstract
Hepatocellular adenomas (HCAs) are benign liver neoplasms which most commonly present in women in their reproductive age. In men, they are rare and have a higher risk of malignant transformation to hepatocellular carcinoma (HCC). Here we present our multicenter experience with HCA in men in the United States. A total of 27 HCA cases were included, with a mean age of presentation of 37 years (range, 9-69 years) and a mean size of 6.8 cm (range, 0.9-18.5 cm). Based on the 2019 World Health Organization classification, the most common subtype identified was inflammatory HCA (IHCA; 10 cases, 37.0%) followed by unclassified HCA (UHCA; 7 cases, 25.9%), HNF1A-inactivated HCA (H-HCA; 6 cases, 22.2%), β-catenin-activated IHCA (b-IHCA; 3 cases, 11.1%), and β-catenin-activated HCA (b-HCA; 1 case, 3.7%). Six additional cases diagnosed as hepatocellular neoplasm of uncertain malignant potential (HUMP) were also included in the study. These cases presented in a mean age of 46 years (range, 17-64 years) and a size of 10.8 cm (range, 4.2-16.5 cm). We evaluated the significance of androgen receptor (AR) expression by immunohistochemistry (IHC); of the 16 cases with materials available, 8 were considered positive using the Allred score system (2 IHCA, 2 H-HCA, 1 UHCA, and 3 HUMP). Of the total cases, 12 were diagnosed on biopsies, for which follow-up information is available for 7, and none of them show evidence of malignant transformation. Of the 21 resection cases, a concomitant well-differentiated HCC within the same lesion was identified in 5 cases (23.8%), which were diagnosed as HCA (n = 4) or HUMP (n = 1). Overall, 15% of cases in our entire cohort of HCA and HUMP showed concomitant HCC, while none of the 7 biopsy cases showed any malignant transformation on follow-up (range, 22-160 months; mean, 61.8 months).
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Affiliation(s)
- Iván A González
- Department of Pathology, Yale University, New Haven, CT, 06520, USA
| | - Michael Torbenson
- Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, 55901, USA
| | - Nima Sharifai
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Kathleen Byrnes
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Deyali Chatterjee
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Sanjay Kakar
- Department of Pathology, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Matthew M Yeh
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | - Tsung-Teh Wu
- Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, 55901, USA
| | - Xuchen Zhang
- Department of Pathology, Yale University, New Haven, CT, 06520, USA
| | - Dhanpat Jain
- Department of Pathology, Yale University, New Haven, CT, 06520, USA.
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13
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Yang KL, Rogers D. Imaging of Hepatocellular Adenomas: From Molecular Biology to MRI. CURRENT RADIOLOGY REPORTS 2022. [DOI: 10.1007/s40134-022-00400-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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14
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Song G, Banov D, Song H, Liu Y, Ip K, Bassani AS, Valdez BC. Evaluation of an Anhydrous Permeation-Enhancing Vehicle for Percutaneous Absorption of Hormones. AAPS PharmSciTech 2022; 23:198. [PMID: 35854200 DOI: 10.1208/s12249-022-02352-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 06/29/2022] [Indexed: 11/30/2022] Open
Abstract
The efficiency and safety of hormone delivery through the skin partly depend on the appropriate choice of vehicle and the type of formulation. The present study reports the skin cytotoxicity, irritancy, and safety of a newly developed anhydrous permeation-enhancing base (APEB) and the percutaneous absorption of progesterone, testosterone, estriol, and estradiol in APEB formulations. Using the human skin EpiDerm model, cell death was not observed after 4 h of exposure to APEB and was 48% after 24 h, indicating its mild to non-irritating property. APEB did not change the expression level of skin cell proliferation markers including PCNA, MCL-1, iNOS, and NFκB proteins, and apoptosis was minimal after 8-h exposure. The in vivo skin irritation and sensitization evaluation of APEB using a Human Repeat Insult Patch Test showed no adverse reaction of any kind during the course of the study. These results indicate the safety of APEB on skin tissues. The hormone percutaneous absorption was performed using human cadaver abdomen skin tissues and the Franz diffusion system, and hormone concentrations were determined by ELISA. Absorption was observed as early as 2 h of application and accumulated after 24 h to 2851 ± 66 ng/cm2, 2338 ± 594 ng/cm2, 55 ± 25 ng/cm2, and 341 ± 122 ng/cm2 for progesterone, testosterone, estriol, and estradiol, respectively. A steady flux rate of absorption of the hormones was observed within 24 h of application. These results suggest that APEB can be used as a vehicle to deliver these hormones through the skin and into the bloodstream for hormone replacement therapy.
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Affiliation(s)
- Guiyun Song
- Professional Compounding Centers of America (PCCA), 9901 South Wilcrest Drive, Houston, Texas, 77099, United States of America.
| | - Daniel Banov
- Professional Compounding Centers of America (PCCA), 9901 South Wilcrest Drive, Houston, Texas, 77099, United States of America
| | - Hui Song
- Professional Compounding Centers of America (PCCA), 9901 South Wilcrest Drive, Houston, Texas, 77099, United States of America
| | - Yi Liu
- Professional Compounding Centers of America (PCCA), 9901 South Wilcrest Drive, Houston, Texas, 77099, United States of America
| | - Kendice Ip
- Professional Compounding Centers of America (PCCA), 9901 South Wilcrest Drive, Houston, Texas, 77099, United States of America
| | - August S Bassani
- Professional Compounding Centers of America (PCCA), 9901 South Wilcrest Drive, Houston, Texas, 77099, United States of America
| | - Benigno C Valdez
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, United States of America
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15
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Petrovic A, Vukadin S, Sikora R, Bojanic K, Smolic R, Plavec D, Wu GY, Smolic M. Anabolic androgenic steroid-induced liver injury: An update. World J Gastroenterol 2022; 28:3071-3080. [PMID: 36051334 PMCID: PMC9331524 DOI: 10.3748/wjg.v28.i26.3071] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/22/2022] [Accepted: 06/18/2022] [Indexed: 02/06/2023] Open
Abstract
Anabolic androgenic steroids (AASs) are a group of molecules including endogenous testosterone and synthetic derivatives that have both androgenic and anabolic effects. These properties make them therapeutically beneficial in medical conditions such as hypogonadism. However, they are commonly bought illegally and misused for their anabolic, skeletal muscle building, and performance-enhancing effects. Supraphysiologic and long-term use of AASs affects all organs, leading to cardiovascular, neurological, endocrine, gastrointestinal, renal, and hematologic disorders. Hepatotoxicity is one of the major concerns regarding AASs treatment and abuse. Testosterone and its derivatives have been most often shown to induce a specific form of cholestasis, peliosis hepatis, and hepatic benign and malignant tumors. It is currently believed that mechanisms of pathogenesis of these disorders include disturbance of antioxidative factors, upregulation of bile acid synthesis, and induction of hepatocyte hyperplasia. Most toxicity cases are treated with supportive measures and liver function normalizes with discontinuation of AAS. However, some long-term consequences are irreversible. AAS-induced liver injury should be taken in consideration in patients with liver disorders, especially with the increasing unintentional ingestion of supplements containing AAS. In this paper, we review the most current knowledge about AAS-associated adverse effects on the liver, and their clinical presentations, prevalence, and pathophysiological mechanisms.
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Affiliation(s)
- Ana Petrovic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek 31000, Croatia
- Department of Pharmacology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek 31000, Croatia
| | - Sonja Vukadin
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek 31000, Croatia
- Department of Pharmacology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek 31000, Croatia
| | - Renata Sikora
- Department of Dental Medicine, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek 31000, Croatia
- Department of Dental Medicine, Health Center Osijek-Baranja County, Osijek 31000, Croatia
| | - Kristina Bojanic
- Department of Otorhinolaryngology, Neurosurgery and Radiology, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek 31000, Croatia
- Department of Biophysics and Radiology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek 31000, Croatia
- Department of Radiology, Health Center Osijek-Baranja County, Osijek 31000, Croatia
| | - Robert Smolic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek 31000, Croatia
| | - Davor Plavec
- Research Department, Srebrnjak Children's Hospital, Zagreb 10000, Croatia
| | - George Y Wu
- Department of Medicine, Division of Gastrenterology/Hepatology, University of Connecticut Health Center, Farmington, CT 06030, United States
| | - Martina Smolic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health Osijek, J. J. Strossmayer University of Osijek, Osijek 31000, Croatia
- Department of Pharmacology, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, Osijek 31000, Croatia
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Pollard JA, Furutani E, Liu S, Esrick E, Cohen LE, Bledsoe J, Liu CW, Lu K, de Haro MJR, Surrallés J, Malsch M, Kuniholm A, Galvin A, Armant M, Kim AS, Ballotti K, Moreau L, Zhou Y, Babushok D, Boulad F, Carroll C, Hartung H, Hont A, Nakano T, Olson T, Sze SG, Thompson AA, Wlodarski MW, Gu X, Libermann TA, D’Andrea A, Grompe M, Weller E, Shimamura A. Metformin for treatment of cytopenias in children and young adults with Fanconi anemia. Blood Adv 2022; 6:3803-3811. [PMID: 35500223 PMCID: PMC9631552 DOI: 10.1182/bloodadvances.2021006490] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 04/15/2022] [Indexed: 11/26/2022] Open
Abstract
Fanconi anemia (FA), a genetic DNA repair disorder characterized by marrow failure and cancer susceptibility. In FA mice, metformin improves blood counts and delays tumor development. We conducted a single institution study of metformin in nondiabetic patients with FA to determine feasibility and tolerability of metformin treatment and to assess for improvement in blood counts. Fourteen of 15 patients with at least 1 cytopenia (hemoglobin < 10 g/dL; platelet count < 100 000 cells/µL; or an absolute neutrophil count < 1000 cells/µL) were eligible to receive metformin for 6 months. Median patient age was 9.4 years (range 6.0-26.5 ). Thirteen of 14 subjects (93%) tolerated maximal dosing for age; 1 subject had dose reduction for grade 2 gastrointestinal symptoms. No subjects developed hypoglycemia or metabolic acidosis. No subjects had dose interruptions caused by toxicity, and no grade 3 or higher adverse events attributed to metformin were observed. Hematologic response based on modified Myelodysplastic Syndrome International Working Group criteria was observed in 4 of 13 evaluable patients (30.8%; 90% confidence interval, 11.3-57.3). Median time to response was 84.5 days (range 71-128 days). Responses were noted in neutrophils (n = 3), platelets (n = 1), and red blood cells (n = 1). No subjects met criteria for disease progression or relapse during treatment. Correlative studies explored potential mechanisms of metformin activity in FA. Plasma proteomics showed reduction in inflammatory pathways with metformin. Metformin is safe and tolerable in nondiabetic patients with FA and may provide therapeutic benefit. This trial was registered at as #NCT03398824.
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Affiliation(s)
- Jessica A. Pollard
- Pediatric Hematology-Oncology, Boston Children’s Hospital, Boston, MA
- Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA
- Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Elissa Furutani
- Pediatric Hematology-Oncology, Boston Children’s Hospital, Boston, MA
- Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA
- Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Shanshan Liu
- Biostatistics and Research Design Center, Institutional Centers for Clinical and Translational Research, Harvard Medical School, Boston, MA
| | - Erica Esrick
- Pediatric Hematology-Oncology, Boston Children’s Hospital, Boston, MA
- Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Laurie E. Cohen
- Department of Pediatrics, Harvard Medical School, Boston, MA
- Department of Endocrinology, and
| | - Jacob Bledsoe
- Department of Pathology, Boston Children’s Hospital, Boston, MA
| | - Chih-Wei Liu
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Kun Lu
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Maria Jose Ramirez de Haro
- Joint Research Unit UAB-Sant Pau Biomedical Research Institute,Institut de Recerca Hospital de la Santa Creu i Sant Pau-IIB Sant Pau, Universitat Autònoma de Barcelona, Barcelona Spain
- Center for Biomedical Network Research on Rare Diseases, Madrid, Spain
| | - Jordi Surrallés
- Joint Research Unit UAB-Sant Pau Biomedical Research Institute,Institut de Recerca Hospital de la Santa Creu i Sant Pau-IIB Sant Pau, Universitat Autònoma de Barcelona, Barcelona Spain
- Center for Biomedical Network Research on Rare Diseases, Madrid, Spain
| | - Maggie Malsch
- Pediatric Hematology-Oncology, Boston Children’s Hospital, Boston, MA
- Clinical Research Operations Center, Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, MA
| | - Ashley Kuniholm
- Clinical Research Operations Center, Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, MA
| | - Ashley Galvin
- Clinical Research Operations Center, Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, MA
| | - Myriam Armant
- Trans Laboratory, Boston Children’s Hospital, Boston, MA
| | - Annette S. Kim
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Kaitlyn Ballotti
- Pediatric Hematology-Oncology, Boston Children’s Hospital, Boston, MA
| | - Lisa Moreau
- Comprehensive Center for Fanconi Anemia, Dana-Farber Cancer Institute, Boston, MA
| | - Yu Zhou
- Pediatric Hematology-Oncology, Boston Children’s Hospital, Boston, MA
| | - Daria Babushok
- Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA
| | - Farid Boulad
- Pediatric Hematology-Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Clint Carroll
- Pediatric Hematology-Oncology, The Children's Hospital at TriStar Centennial, Nashville, TN
| | - Helge Hartung
- Pediatric Hematology-Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Amy Hont
- Pediatric Hematology-Oncology, Children’s National Medical Center, Washington, DC
| | - Taizo Nakano
- Pediatric Hematology-Oncology, Children’s Hospital Colorado, Denver, CO
| | - Tim Olson
- Pediatric Hematology-Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Sei-Gyung Sze
- Department of Pediatrics, Maine Medical Center, Tufts University School of Medicine, Portland, ME
| | - Alexis A. Thompson
- Pediatric Hematology-Oncology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL
| | - Marcin W. Wlodarski
- Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN
| | - Xuesong Gu
- Beth Israel Deaconess Medical Center Genomics, Proteomics, Bioinformatics and Systems Biology Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
| | - Towia A. Libermann
- Beth Israel Deaconess Medical Center Genomics, Proteomics, Bioinformatics and Systems Biology Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
| | - Alan D’Andrea
- Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Markus Grompe
- Oregon Stem Cell Center, Department of Pediatrics, Papé Family Institute, Oregon Health and Science University, Portland, OR; and
| | - Edie Weller
- Department of Pediatrics, Harvard Medical School, Boston, MA
- Biostatistics and Research Design Center, Institutional Centers for Clinical and Translational Research, Harvard Medical School, Boston, MA
| | - Akiko Shimamura
- Pediatric Hematology-Oncology, Boston Children’s Hospital, Boston, MA
- Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA
- Department of Pediatrics, Harvard Medical School, Boston, MA
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Oudmaijer CAJ, Berk KA, van der Louw EJTM, de Man R, van der Lelij AJ, Hoeijmakers JHJ, IJzermans J. KETOgenic diet therapy in patients with HEPatocellular adenoma: study protocol of a matched interventional cohort study. BMJ Open 2022; 12:e053559. [PMID: 35168973 PMCID: PMC8852750 DOI: 10.1136/bmjopen-2021-053559] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
INTRODUCTION Hepatocellular adenoma (HCA) is an uncommon, solid and benign liver lesion, mainly occurring in women using oral contraceptives. Patients are advised to stop using oral contraceptives (OC) and, as overweight is frequently observed, dietary restrictions. Metabolic changes are assumed to play a role and it has been suggested that diet may help to reduce tumour size. A low-calorie ketogenic diet (LCKD) has been shown to induce weight loss and multiple metabolic changes, including the reduction of portal insulin concentrations, which downregulates hepatic growth hormone receptors. Weight reduction and an LCKD can potentially reduce the size of HCAs. METHODS AND ANALYSIS We designed a matched, interventional cohort study to determine the effect of an LCKD on the regression of HCA. The study population consists of female subjects with an HCA, 18-50 years of age, body mass index>25 kg/m2, who are entering a surveillance period including cessation of OC. A historical control group will be matched. The intervention consists of an LCKD (approximately 35 g carbohydrate/1500 kcal/day) for 3 months, followed by a less strict LCKD for 3 months (approximately 60 g carbohydrate/1500 kcal/day). Main study endpoint is the diameter of the HCA after 6 months, as compared with the historic control group. Secondary endpoints include adherence, quality of life, change in physical activity, liver fat content, body weight, body composition and resting energy expenditure. ETHICS AND DISSEMINATION The medical ethical committee has approved the study protocol, patient information files and consent procedure and other study-related documents and procedures. TRIAL REGISTRATION NUMBER NL75014.078.20; Pre-results. https://www.trialregister.nl/trial/9092.
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Affiliation(s)
- Christiaan Albert Johan Oudmaijer
- Erasmus MC Transplant Institute, Department of Surgery, Division of Hepatobiliary and Transplantation Surgery, Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands
- Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Kirsten Anna Berk
- Department of Internal Medicine, Division of Dietetics, Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands
| | | | - Rob de Man
- Department of Hepato-Gastroenterology, Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands
| | - Aart-Jan van der Lelij
- Department of Internal Medicine, Division of Endocrinology, Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands
| | - Jan Hendrik Jozef Hoeijmakers
- Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Erasmus MC Cancer Institute, Department of Molecular Genetics, Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands
| | - Jan IJzermans
- Erasmus MC Transplant Institute, Department of Surgery, Division of Hepatobiliary and Transplantation Surgery, Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands
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18
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Bioulac-Sage P, Gouw ASH, Balabaud C, Sempoux C. Hepatocellular Adenoma: What We Know, What We Do Not Know, and Why It Matters. Histopathology 2021; 80:878-897. [PMID: 34856012 DOI: 10.1111/his.14605] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/21/2021] [Accepted: 11/25/2021] [Indexed: 11/27/2022]
Abstract
In the last 2 decades there has been significant progress in research and diagnosis of hepatocellular adenoma (HCA), resulting in the establishment of a molecular and immunohistological HCA classification. This review aims to fine-tune the current expertise in order to enhance the histopathological diagnostic possibilities, by refining issues that are already known, addressing diagnostic difficulties and identifying still unknown aspects of HCA. We will discuss novel methods to identify HCA subtypes, in particular the sonic hedgehog HCAs and the interpretation of glutamine synthetase patterns for the recognition of beta-catenin mutated HCAs. The major complications of HCAs, bleeding and malignant transformation, will be considered, including the dilemmas of atypical and borderline lesions. Paragraphs on HCAs in different clinical and geographical settings, e.g. pregnancy, cirrhosis and non-western countries are included. The natural history of the different HCA subtypes in relation with age, sex and risk factors is a feature still insufficiently investigated. This is also true for the risks of clinical bleeding and malignant transformation in association with HCA subtypes. As HCA is a relatively rare tumor, a multicenter and multidisciplinary approach across geographical boundaries will be the appropriate method to establish prospective programs to identify, classify and manage HCAs, focusing on several aspects, e.g. etiology, underlying liver disease, complications, regression and growth. Updating what we know, identifying and addressing features that we do not know matters to warrant optimal patient management.
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Affiliation(s)
| | - Annette S H Gouw
- Departement of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands
| | | | - Christine Sempoux
- Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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19
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Morozova MM, Ivanova EI, Chardarov NK, Dolzhanskiy OV, Shatveryan GA, Kamalov YR. [Multiple hepatocellular adenomas and renal cell carcinoma associated with anabolic androgenic steroids]. Khirurgiia (Mosk) 2021:105-109. [PMID: 34608788 DOI: 10.17116/hirurgia2021101105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The authors report a rare case of combination of chromophobe renal cell carcinoma Grade 2 pT2aN0 with multiple hepatocellular adenomas in a 31-year-old bodybuilder who received anabolic androgenic steroids at high doses for 8 years. According to MRI data, over 15 liver adenomas and tumor in the lower segment of the right kidney were detected. The patients underwent laparascopic resection of the right kidney and liver segments 2, 3 and 4 with large adenomas. Histological study and immunohistochemistry revealed no malignancy signs in hepatocellular adenomas. Nuclear β-catenin expression was absent. Kidney tumor had a structure of chromophobe renal cell carcinoma. The patient is currently being followed-up due to residual small liver adenomas. In our opinion, liver adenomatosis and renal cancer have the same cause in this case (chronic toxic effect of androgens).
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Affiliation(s)
- M M Morozova
- Petrovsky Russian Research Center of Surgery, Moscow, Russia
| | - E I Ivanova
- Petrovsky Russian Research Center of Surgery, Moscow, Russia
| | - N K Chardarov
- Petrovsky Russian Research Center of Surgery, Moscow, Russia
| | - O V Dolzhanskiy
- Petrovsky Russian Research Center of Surgery, Moscow, Russia
| | - G A Shatveryan
- Petrovsky Russian Research Center of Surgery, Moscow, Russia
| | - Yu R Kamalov
- Petrovsky Russian Research Center of Surgery, Moscow, Russia
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20
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Vieri M, Brümmendorf TH, Beier F. Treatment of telomeropathies. Best Pract Res Clin Haematol 2021; 34:101282. [PMID: 34404536 DOI: 10.1016/j.beha.2021.101282] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 06/22/2021] [Accepted: 06/25/2021] [Indexed: 10/21/2022]
Abstract
Telomeropathies or telomere biology disorders (TBDs) are a group of rare diseases characterised by altered telomere maintenance. Most patients with TBDs show pathogenic variants of genes that encode factors involved in the prevention of telomere shortening. Particularly in adults, TBDs mostly present themselves with heterogeneous clinical features that often include bone marrow failure, hepatopathies, interstitial lung disease and other organ sites. Different degrees of severity are also observed among patients with TBDs, ranging from very severe syndromes manifesting themselves in early childhood, such as Revesz syndrome, Hoyeraal-Hreidarsson syndrome, and Coats plus disease, to dyskeratosis congenita (DKC) and adult-onset "cryptic" forms of TBD, which often affect fewer organ systems. Overall, the most relevant clinical complications of TBD are bone marrow failure, lung fibrosis, and liver cirrhosis. In this review, we summarise recent advances in the management and treatment of TBD and provide a brief overview of the various treatment approaches.
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Affiliation(s)
- Margherita Vieri
- Department of Hematology, Oncology, Hemostaseology, Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany.
| | - Tim H Brümmendorf
- Department of Hematology, Oncology, Hemostaseology, Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany.
| | - Fabian Beier
- Department of Hematology, Oncology, Hemostaseology, Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Germany.
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21
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Abstract
Androgens are potent drugs requiring prescription for valid medical indications but are misused for invalid, unproven, or off-label reasons as well as being abused without prescription for illicit nonmedical application for performance or image enhancement. Following discovery and first clinical application of testosterone in the 1930s, commercialization of testosterone and synthetic androgens proliferated in the decades after World War II. It remains among the oldest marketed drugs in therapeutic use, yet after 8 decades of clinical use, the sole unequivocal indication for testosterone remains in replacement therapy for pathological hypogonadism, organic disorders of the male reproductive system. Nevertheless, wider claims assert unproven, unsafe, or implausible benefits for testosterone, mostly representing wishful thinking about rejuvenation. Over recent decades, this created an epidemic of testosterone misuse involving prescription as a revitalizing tonic for anti-aging, sexual dysfunction and/or obesity, where efficacy and safety remains unproven and doubtful. Androgen abuse originated during the Cold War as an epidemic of androgen doping among elite athletes for performance enhancement before the 1980s when it crossed over into the general community to become an endemic variant of drug abuse in sufficiently affluent communities that support an illicit drug industry geared to bodybuilding and aiming to create a hypermasculine body physique and image. This review focuses on the misuse of testosterone, defined as prescribing without valid clinical indications, and abuse of testosterone or synthetic androgens (androgen abuse), defined as the illicit use of androgens without prescription or valid indications, typically by athletes, bodybuilders and others for image-oriented, cosmetic, or occupational reasons.
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Affiliation(s)
- David J Handelsman
- ANZAC Research Institute, University of Sydney, Sydney, Australia.,Andrology Department, Concord Hospital, Sydney, Australia
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22
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Life-Threatening Intraparenchymal Hemorrhage of Steroid-Induced Hepatic Adenomas in a Healthy Man. ACG Case Rep J 2021; 8:e00601. [PMID: 34046510 PMCID: PMC8148419 DOI: 10.14309/crj.0000000000000601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 02/16/2021] [Indexed: 11/18/2022] Open
Abstract
Hepatocellular adenomas are uncommon benign epithelial tumors of the liver that are associated with several risk factors such as anabolic androgens and oral contraceptive pills. They may present as incidental findings, with abdominal pain or hemorrhage. This case report details the presentation and management of a life-threatening hepatocellular adenomas hemorrhage in a seemingly healthy 28-year-old man. After initial conservative management, a clinical deterioration prompted urgent reevaluation and successful embolization of the liver through transarterial embolization. As oral contraceptive pills use and anabolic steroid abuse have become more prevalent in recent decades, we may begin to see more of these presentations.
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23
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Shafaee Z, Liu S, Fiel MI, Blue R. Giant pedunculated hepatocellular adenoma masquerading as a subdiaphragmatic mass: Diagnostic challenges of a rare tumor. Radiol Case Rep 2021; 16:84-89. [PMID: 33193934 PMCID: PMC7644822 DOI: 10.1016/j.radcr.2020.10.047] [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: 09/03/2020] [Revised: 10/20/2020] [Accepted: 10/23/2020] [Indexed: 11/28/2022] Open
Abstract
Giant pedunculated hepatocellular adenomas are extremely rare tumors and often detected incidentally on cross-sectional imaging studies. We report the case of a 34-year-old woman who underwent cross-sectional imaging for staging evaluation of a uterine tumor. A large left subdiaphragmatic mass, without clear connection to the liver, was seen prompting diagnostic laparoscopy; during which a large pedunculated mass attached to the left lobe of the liver was found and resected. This case report highlights the challenges and pitfalls in the imaging diagnosis of pedunculated hepatocellular adenomas, such as difficulty in characterizing the mass or inability to identify the vascular attachment to the liver. Image-guided biopsy and diagnostic laparoscopy are valuable tools to establish diagnosis; most of these lesions are amenable to laparoscopic resection.
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Affiliation(s)
- Zahra Shafaee
- Department of Surgery, NYC Health + Hospitals/Elmhurst, 79-01 Broadway, Elmhurst, NY 11373, USA
| | - Shaojun Liu
- Department of Pathology, NYC Health + Hospitals/Elmhurst, 79-01 Broadway, Elmhurst, NY 11373, USA
| | - Maria Isabel Fiel
- Department of Pathology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Pl, New York, NY 10029, USA
| | - Robert Blue
- Department of Radiology, NYC Health + Hospitals/Elmhurst, 79-01 Broadway, Elmhurst, NY 11373, USA
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24
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Comparable Effects of the Androgen Derivatives Danazol, Oxymetholone and Nandrolone on Telomerase Activity in Human Primary Hematopoietic Cells from Patients with Dyskeratosis Congenita. Int J Mol Sci 2020; 21:ijms21197196. [PMID: 33003434 PMCID: PMC7584039 DOI: 10.3390/ijms21197196] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/26/2020] [Accepted: 09/27/2020] [Indexed: 12/11/2022] Open
Abstract
Dyskeratosis congenita (DKC) is a rare inherited disease of impaired telomere maintenance that progressively leads to multi-organ failure, including the bone marrow. By enhancing telomerase activity, androgen derivatives (ADs) are a potential therapeutic option able to re-elongate previously shortened telomeres. Danazol, oxymetholone, and nandrolone are ADs most frequently used to treat DKC. However, no direct in vitro analyses comparing the efficacy of these ADs have been conducted so far. We therefore treated mononuclear cells derived from peripheral blood and bone marrow of four patients with mutations in telomerase reverse transcriptase (TERT, n = 1),in the telomerase RNA component (TERC, n = 2) and in dyskerin pseudouridine synthase 1 (DKC1, n = 1) and found no substantial differences in the activity of these three agents in patients with TERC/TERT mutations. All AD studied produced comparable improvements of proliferation rates as well as degrees of telomere elongation. Increased TERT expression levels were shown with danazol and oxymetholone. The beneficial effects of all ADs on proliferation of bone marrow progenitors could be reversed by tamoxifen, an estrogen antagonist abolishing estrogen receptor-mediated TERT expression, thereby underscoring the involvement of TERT in AD mechanism of action. In conclusion, no significant differences in the ability to functionally enhance telomerase activity could be observed for the three AD studied in vitro. Physicians therefore might choose treatment based on patients’ individual co-morbidities, e.g., pre-existing liver disease and expected side-effects.
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Abstract
Drug induced liver injury (DILI) is a relatively rare hepatic condition in response to the use of medications, illegal drugs, herbal products or dietary supplements. It occurs in susceptible individuals through a combination of genetic and environmental risk factors believed to modify drug metabolism and/or excretion leading to a cascade of cellular events, including oxidative stress formation, apoptosis/necrosis, haptenization, immune response activation and a failure to adapt. The resultant liver damage can present with an array of phenotypes, which mimic almost every other liver disorder, and varies in severity from asymptomatic elevation of liver tests to fulminant hepatic failure. Despite recent research efforts specific biomarkers are not still available for routine use in clinical practice, which makes the diagnosis of DILI uncertain and relying on a high degree of awareness of this condition and the exclusion of other causes of liver disease. Diagnostic scales such as the CIOMS/RUCAM can support the causality assessment of a DILI suspicion, but need refinement as some criteria are not evidence-based. Prospective collection of well-vetted DILI cases in established DILI registries has allowed the identification and validation of a number of clinical variables, and to predict a more severe DILI outcome. DILI is also in need of properly designed clinical trials to evaluate the efficacy of new DILI treatments as well as older drugs such as ursodeoxycholic acid traditionally used to ameliorate cholestasis or corticosteroids now widely tried in the oncology field to manage the emergent type of hepatotoxicity related to immune checkpoint inhibitors.
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26
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Rageul J, Kim H. Fanconi anemia and the underlying causes of genomic instability. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2020; 61:693-708. [PMID: 31983075 PMCID: PMC7778457 DOI: 10.1002/em.22358] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 01/03/2020] [Accepted: 01/21/2020] [Indexed: 05/02/2023]
Abstract
Fanconi anemia (FA) is a rare genetic disorder, characterized by birth defects, progressive bone marrow failure, and a predisposition to cancer. This devastating disease is caused by germline mutations in any one of the 22 known FA genes, where the gene products are primarily responsible for the resolution of DNA interstrand cross-links (ICLs), a type of DNA damage generally formed by cytotoxic chemotherapeutic agents. However, the identity of endogenous mutagens that generate DNA ICLs remains largely elusive. In addition, whether DNA ICLs are indeed the primary cause behind FA phenotypes is still a matter of debate. Recent genetic studies suggest that naturally occurring reactive aldehydes are a primary source of DNA damage in hematopoietic stem cells, implicating that they could play a role in genome instability and FA. Emerging lines of evidence indicate that the FA pathway constitutes a general surveillance mechanism for the genome by protecting against a variety of DNA replication stresses. Therefore, understanding the DNA repair signaling that is regulated by the FA pathway, and the types of DNA lesions underlying the FA pathophysiology is crucial for the treatment of FA and FA-associated cancers. Here, we review recent advances in our understanding of the relationship between reactive aldehydes, bone marrow dysfunction, and FA biology in the context of signaling pathways triggered during FA-mediated DNA repair and maintenance of the genomic integrity. Environ. Mol. Mutagen. 2020. © 2020 Wiley Periodicals, Inc.
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Affiliation(s)
- Julie Rageul
- Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794, USA
| | - Hyungjin Kim
- Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794, USA
- Stony Brook Cancer Center, Renaissance School of Medicine at Stony Brook University, Stony Brook, New York 11794, USA
- Correspondence to: Hyungjin Kim, Ph.D., Department of Pharmacological Sciences, Renaissance School of Medicine at Stony Brook University, Basic Sciences Tower 8-125, 100 Nicolls Rd., Stony Brook, NY 11794, Phone: 631-444-3134, FAX: 631-444-3218,
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27
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Hahn E, Putra J. Hepatocellular adenoma in the paediatric population: Molecular classification and clinical associations. World J Gastroenterol 2020; 26:2294-2304. [PMID: 32476794 PMCID: PMC7243640 DOI: 10.3748/wjg.v26.i19.2294] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/29/2020] [Accepted: 05/01/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular adenomas (HCAs) represent rare, benign liver tumours occurring predominantly in females taking oral contraceptives. In children, HCAs comprise less than 5% of hepatic tumours and demonstrate association with various conditions. The contemporary classification of HCAs, based on their distinctive genotypes and clinical phenotypes, includes hepatocyte nuclear factor 1 homeobox alpha-inactivated HCAs, beta-catenin-mutated HCAs, inflammatory HCAs, combined beta-catenin-mutated and inflammatory HCAs, sonic hedgehog-activated HCAs, and unclassified HCAs. In children, there is a lack of literature on the characteristics and distribution of HCA subtypes. In this review, we summarized different HCA subtypes and the clinicopathologic spectrum of HCAs in the paediatric population.
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Affiliation(s)
- Elan Hahn
- Division of Pathology, Department of Paediatric Laboratory Medicine, the Hospital for Sick Children, Toronto M5G 1X8, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto M5S 1A8, ON, Canada
| | - Juan Putra
- Division of Pathology, Department of Paediatric Laboratory Medicine, the Hospital for Sick Children, Toronto M5G 1X8, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto M5S 1A8, ON, Canada
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28
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Impact of Epigenetics on Complications of Fanconi Anemia: The Role of Vitamin D-Modulated Immunity. Nutrients 2020; 12:nu12051355. [PMID: 32397406 PMCID: PMC7285109 DOI: 10.3390/nu12051355] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/02/2020] [Accepted: 05/06/2020] [Indexed: 12/14/2022] Open
Abstract
Fanconi anemia (FA) is a rare disorder with the clinical characteristics of (i) specific malformations at birth, (ii) progressive bone marrow failure already during early childhood and (iii) dramatically increased risk of developing cancer in early age, such as acute myeloid leukemia and squamous cell carcinoma. Patients with FA show DNA fragility due to a defect in the DNA repair machinery based on predominately recessive mutations in 23 genes. Interestingly, patients originating from the same family and sharing an identical mutation, frequently show significant differences in their clinical presentation. This implies that epigenetics plays an important role in the manifestation of the disease. The biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 controls cellular growth, differentiation and apoptosis via the modulation of the immune system. The nuclear hormone activates the transcription factor vitamin D receptor that affects, via fine-tuning of the epigenome, the transcription of >1000 human genes. In this review, we discuss that changes in the epigenome, in particular in immune cells, may be central for the clinical manifestation of FA. These epigenetic changes can be modulated by vitamin D suggesting that the individual FA patient’s vitamin D status and responsiveness are of critical importance for disease progression.
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29
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Català A, Ali SS, Cuvelier GDE, Steele M, Klaassen RJ, Fernandez CV, Pastore YD, Abish S, Rayar M, Jardine L, Breakey VR, Brossard J, Sinha R, Silva M, Goodyear L, Lipton JH, Michon B, Corriveau-Bourque C, Sung L, Lauhasurayotin S, Zlateska B, Cada M, Dror Y. Androgen therapy in inherited bone marrow failure syndromes: analysis from the Canadian Inherited Marrow Failure Registry. Br J Haematol 2020; 189:976-981. [PMID: 32128787 DOI: 10.1111/bjh.16445] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Accepted: 11/21/2019] [Indexed: 11/29/2022]
Abstract
Progressive cytopenia is a serious complication among paediatric patients with inherited bone marrow failure syndromes (IBMFS). Androgens have been used to improve blood counts in different bone marrow failure conditions. Little is known about efficacy and toxicity with new androgens (i.e., danazol) in different types of IBMFS. We identified 29 patients from the Canadian Inherited Marrow Failure Registry, who received oxymetholone or danazol. Sixteen (55%) had haematological response including patients with unclassified IBMFS (45%). Danazol showed a better toxicity profile and similar efficacy compared to oxymetholone. Androgens are an effective and safe option to ameliorate bone marrow failure in IBMFS.
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Affiliation(s)
- Albert Català
- Division of Hematology/Oncology, Department of Pediatrics, Marrow Failure and Myelodysplasia Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Salah S Ali
- Bone Marrow Transplantation and Cellular Therapy, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada
| | - Geoffrey D E Cuvelier
- Pediatric Hematology-Oncology-Blood and Marrow Transplantation, University of Manitoba, CancerCare Manitoba, Winnipeg, MB, Canada
| | | | - Robert J Klaassen
- Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada
| | | | | | - Sharon Abish
- Pediatric Hematology Oncology, Montreal Children's Hospital, Montreal, QC, Canada
| | - Meera Rayar
- Division of Hematology/Oncology, UBC & B.C. Children's Hospital, Vancouver, BC, Canada
| | - Lawrence Jardine
- Children's Hospital, London Health Sciences Centre, London, ON, Canada
| | - Vicky R Breakey
- Department of Pediatrics, McMaster University, Hamilton, ON, Canada
| | - Josee Brossard
- Centre Hospitalier Universitaire, Sherbrooke, QC, Canada
| | - Roona Sinha
- Royal University Hospital, Saskatoon, SK, Canada
| | | | - Lisa Goodyear
- Pediatric Hematology/Oncology, Janeway Child Health Centre, St. John's, NF, Canada
| | - Jeffrey H Lipton
- Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Bruno Michon
- Centre Hospitalier Universitaire de Quebec, Sainte-Foy, QC, Canada
| | | | - Lillian Sung
- Division of Hematology/Oncology, Department of Pediatrics, Child and Population Health Sciences, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada
| | - Supanun Lauhasurayotin
- Division of Hematology/Oncology, Department of Pediatrics, Marrow Failure and Myelodysplasia Program, The Hospital for Sick Children, Toronto, ON, Canada.,Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Bozana Zlateska
- Division of Hematology/Oncology, Department of Pediatrics, Marrow Failure and Myelodysplasia Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Michaela Cada
- Division of Hematology/Oncology, Department of Pediatrics, Marrow Failure and Myelodysplasia Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Yigal Dror
- Division of Hematology/Oncology, Department of Pediatrics, Marrow Failure and Myelodysplasia Program, The Hospital for Sick Children, Toronto, ON, Canada.,Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.,Institute of Medical Science, University of Toronto, Toronto, ON, Canada
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30
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Andrade RJ, Robles-Díaz M. Diagnostic and prognostic assessment of suspected drug-induced liver injury in clinical practice. Liver Int 2020; 40:6-17. [PMID: 31578817 DOI: 10.1111/liv.14271] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 09/17/2019] [Accepted: 09/19/2019] [Indexed: 02/13/2023]
Abstract
Idiosyncratic drug-induced liver injury (DILI) is a challenging liver disorder because it can present with a range of phenotypes, mimicking almost every other hepatic disease, and lacks specific biomarkers for its diagnosis. Hence, a confident DILI diagnosis is seldom possible as it relies on the precise establishment of a temporal sequence between the exposure to a given prescription drug or sometimes hidden herbal product/over the counter medication as well as the exclusion of other aetiologies of liver disease. However, an accurate diagnosis is of most importance, as prompt withdrawal of the causative agent is essential in DILI management. Indeed, DILI can be severe and even fatal or in a fraction of cases evolve to chronic damage, but specific biomarkers for predicting mortality/liver transplantation or a chronic outcome in the very early phases of DILI are not yet available. In this article, we discuss the best diagnostic and prognostic approach of a DILI suspicion by judiciously choosing and interpreting the standard tests currently used in clinical practice.
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Affiliation(s)
- Raúl J Andrade
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Universidad de Málaga, Malaga, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Mercedes Robles-Díaz
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Universidad de Málaga, Malaga, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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31
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Zulfiqar M, Sirlin CB, Yoneda N, Ronot M, Hecht EM, Chernyak V, Matsui O, Bastati N, Ba‐Ssalamah A, Chatterjee D, Bashir M, Fowler KJ. Hepatocellular adenomas: Understanding the pathomolecular lexicon, MRI features, terminology, and pitfalls to inform a standardized approach. J Magn Reson Imaging 2019; 51:1630-1640. [DOI: 10.1002/jmri.26902] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 08/02/2019] [Accepted: 08/05/2019] [Indexed: 12/15/2022] Open
Affiliation(s)
- Maria Zulfiqar
- Mallinckrodt Institute of RadiologyWashington University School of Medicine St Louis Missouri USA
| | - Claude B. Sirlin
- Department of RadiologyUniversity of California San Diego San Diego California USA
| | | | - Maxime Ronot
- Department of RadiologyHôpitaux Universitaires Paris Nord Val de Seine, Cinchy France
| | | | - Victoria Chernyak
- Department of Radiology, Montefiore Medical CenterAlbert Einstein College of Medicine New York New York USA
| | - Osamu Matsui
- Department of RadiologyKanazawa University Japan
| | - Nina Bastati
- Department of Biomedical Imaging and Image‐guided therapyMedical University of Vienna Vienna Austria
| | - Ahmed Ba‐Ssalamah
- Department of Biomedical Imaging and Image‐guided therapyMedical University of Vienna Vienna Austria
| | - Deyali Chatterjee
- Department of PathologyWashington University School of Medicine St Louis Missouri USA
| | - Mustafa Bashir
- Department of RadiologyDuke University Durham North Carolina USA
| | - Kathryn J. Fowler
- Department of RadiologyUniversity of California San Diego San Diego California USA
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32
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Liver-specific androgen receptor knockout attenuates early liver tumor development in zebrafish. Sci Rep 2019; 9:10645. [PMID: 31337771 PMCID: PMC6650507 DOI: 10.1038/s41598-019-46378-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 06/10/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most severe cancer types and many genetic and environmental factors contribute to the development of HCC. Androgen receptor (AR) signaling is increasingly recognized as one of the important factors associated with HCC. Previously, we have developed an inducible HCC model in kras transgenic zebrafish. In the present study, to investigate the role of AR in liver tumor development, we specifically knocked out ar gene in the liver of zebrafish via the CRISPR/Cas9 system and the knockout zebrafish was named L-ARKO for liver-specific ar knockout. We observed that liver-specific knockout of ar attenuated liver tumor development in kras transgenic zebrafish at the early stage (one week of tumor induction). However, at the late stage (two weeks of tumor induction), essentially all kras transgenic fish continue to develop HCC irrespective of the absence or presence of ar gene, indicating an overwhelming role of the driver oncogene kras over ar knockout. Consistently, cell proliferation was reduced at the early stage, but not the late stage, of liver tumor induction in the kras/L-ARKO fish, indicating that the attenuant effect of ar knockout was at least in part via cell proliferation. Furthermore, androgen treatment showed acceleration of HCC progression in kras fish but not in kras/L-ARKO fish, further indicating the abolishment of ar signalling. Therefore, we have established a tissue-specific ar knockout zebrafish and it should be a valuable tool to investigate AR signalling in the liver in future.
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Koya Y, Suzuki T, Tai M, Ichii O, Matsuhashi N, Ejiri Y, Miyazawa M, Shibata M, Harada M, Kumabe T, Nakashima O. Inflammatory Hepatocellular Adenoma with Elevated Serum Protein Induced by Vitamin K Absence/Antagonist-II in Adult Males. Intern Med 2019; 58:1739-1746. [PMID: 30799343 PMCID: PMC6630141 DOI: 10.2169/internalmedicine.1958-18] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Two men (24 and 34 years of age) with a single hypervascular liver tumor were admitted to our hospital. The tumors were diagnosed as hepatocellular adenoma (HCA) by an ultrasound-guided biopsy and classified as inflammatory type by immunohistochemical staining. Considering the risk of malignant transformation, they underwent surgical resection. Although the serum levels of protein induced by vitamin K absence/antagonist-II (PIVKA-II) were slightly elevated, they normalized after the resection. The diagnosis of HCA including malignant transformation is often difficult by image findings alone. Careful immunohistochemical examinations are very useful for the diagnosis and classification of subgroups, including malignant transformation. In addition, we proved that HCA without malignant transformation expresses PIVKA-II.
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Affiliation(s)
- Yudai Koya
- The Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan
| | - Tomohiro Suzuki
- Department of Gastroenterology, Fukushima Rosai Hospital, Japan
| | - Mayumi Tai
- Department of Gastroenterology, Fukushima Rosai Hospital, Japan
| | - Osamu Ichii
- Department of Gastroenterology, Fukushima Rosai Hospital, Japan
| | | | - Yutaka Ejiri
- Department of Gastroenterology, Fukushima Rosai Hospital, Japan
| | | | - Michihiko Shibata
- The Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan
| | - Masaru Harada
- The Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan
| | | | - Osamu Nakashima
- Department of Clinical Laboratory Medicine, Kurume University Hospital, Japan
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Andrade RJ, Aithal GP, Björnsson ES, Kaplowitz N, Kullak-Ublick GA, Larrey D, Karlsen TH. EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol 2019; 70:1222-1261. [PMID: 30926241 DOI: 10.1016/j.jhep.2019.02.014] [Citation(s) in RCA: 646] [Impact Index Per Article: 107.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 02/14/2019] [Indexed: 02/07/2023]
Abstract
Idiosyncratic (unpredictable) drug-induced liver injury is one of the most challenging liver disorders faced by hepatologists, because of the myriad of drugs used in clinical practice, available herbs and dietary supplements with hepatotoxic potential, the ability of the condition to present with a variety of clinical and pathological phenotypes and the current absence of specific biomarkers. This makes the diagnosis of drug-induced liver injury an uncertain process, requiring a high degree of awareness of the condition and the careful exclusion of alternative aetiologies of liver disease. Idiosyncratic hepatotoxicity can be severe, leading to a particularly serious variety of acute liver failure for which no effective therapy has yet been developed. These Clinical Practice Guidelines summarize the available evidence on risk factors, diagnosis, management and risk minimization strategies for drug-induced liver jury.
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Li H, Lu JW, Huo X, Li Y, Li Z, Gong Z. Effects of sex hormones on liver tumor progression and regression in Myc/xmrk double oncogene transgenic zebrafish. Gen Comp Endocrinol 2019; 277:112-121. [PMID: 30926469 DOI: 10.1016/j.ygcen.2019.03.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 03/21/2019] [Accepted: 03/24/2019] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) shows clear sex disparity with men being more prone to developing HCC and having higher mortality than women. Previous studies have indicated that sex hormones play important roles in HCC initiation and development, but the effects of sex hormones on HCC in clinical trials remain inconsistent. Using zebrafish liver tumor model co-induced by oncogenes Myc and xmrk, we observed similar sex disparity between male and female zebrafish in liver tumor progression and regression; i.e. male Myc/xmrk transgenic zebrafish developed HCC significantly faster and regressed HCC significantly slower than female Myc/xmrk transgenic zebrtafish. To investigate the effects of sex hormones on liver tumor progression and regression, Myc/xmrk fish were treated with either androgen or estrogen, we observed that androgen promoted HCC progression and retarded HCC regression in females, while estrogen attenuated HCC progression and accelerated HCC regression in males. Furthermore, androgen promoted cell proliferation while estrogen inhibited it. Overall, the present study suggested that sex hormones affected liver tumor progression and regression in the Myc/xmrk transgenic zebrafish.
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Affiliation(s)
- Hankun Li
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Jeng-Wei Lu
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Xiaojing Huo
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Yan Li
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Zhen Li
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Zhiyuan Gong
- Department of Biological Sciences, National University of Singapore, Singapore.
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Woodward C, Smith J, Acreman D, Kumar N. Hepatocellular carcinoma in body builders; an emerging rare but serious complication of androgenic anabolic steroid use. Ann Hepatobiliary Pancreat Surg 2019; 23:174-177. [PMID: 31225420 PMCID: PMC6558130 DOI: 10.14701/ahbps.2019.23.2.174] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 03/03/2019] [Accepted: 03/29/2019] [Indexed: 02/07/2023] Open
Abstract
Illicit use of androgenic anabolic steroids (AAS) is a known problem amongst certain groups including body builders and other athletes. Use of these drugs is thought to be high in some areas of South Wales. A number of adverse effects have been associated with use of AAS including the development of hepatic adenomas. There have been a handful of rare cases of the development of hepatocellular carcinoma following AAS use. We report two such cases presenting to the same surgical centre in South Wales within six months. We do this with reference to data from Public Health Wales, including the Harm Reduction Wales Needle and Syringe provision report, which indicate a particularly high rate of use of AAS in the surrounding area. We believe these cases are important from the public health point of view. They demonstrate a rare and not widely known about, but potentially fatal adverse effect of AAS, now becoming prevalent with the high use of these drugs. This is important for doctors to be aware of, but also could form the focus of a public health campaign targeted at AAS users.
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Affiliation(s)
| | - Josie Smith
- University Hospital Wales, and Public Health Wales, Cardiff, UK
| | - Dean Acreman
- University Hospital Wales, and Public Health Wales, Cardiff, UK
| | - Nagappan Kumar
- University Hospital Wales, and Public Health Wales, Cardiff, UK
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Engel NW, Schliffke S, Schüller U, Frenzel C, Bokemeyer C, Kubisch C, Lessel D. Fatal Myelotoxicity Following Palliative Chemotherapy With Cisplatin and Gemcitabine in a Patient With Stage IV Cholangiocarcinoma Linked to Post Mortem Diagnosis of Fanconi Anemia. Front Oncol 2019; 9:420. [PMID: 31192125 PMCID: PMC6540739 DOI: 10.3389/fonc.2019.00420] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 05/03/2019] [Indexed: 12/16/2022] Open
Abstract
Unrecognized genome instability syndromes can potentially impede the rational treatment of cancer in rare patients. Identification of cancer patients with a hereditary condition is a compelling necessity for oncologists, giving varying hypersensitivities to various chemotherapeutic agents or radiation, depending on the underlying genetic cause. Omission of genetic testing in the setting of an overlooked hereditary syndrome may lead to unexpected and unbearable toxicity from oncological standard approaches. We present a case of a 33-year-old man with an early-onset stage IV intrahepatic cholangiocarcinoma, who experienced unusual bone marrow failure and neutropenic fever syndrome as a consequence of palliative chemotherapy containing cisplatin and gemcitabine, leading to a fatal outcome on day 25 of his first chemotherapeutic cycle. The constellation of bone marrow failure after exposure to the platinum-based agent cisplatin, the presence of an early-onset solid malignancy and the critical appraisal of further phenotypical features raised suspicion of a hereditary genome instability syndrome. Whole-exome sequencing from buccal swab DNA enabled the post mortem diagnosis of Fanconi anemia, most likely linked to the fatal outcome due to utilization of the DNA crosslinking agent cisplatin. The patient's phenotype was exceptional, as he never displayed significant hematologic abnormalities, which is the hallmark of Fanconi anemia. As such, this case stresses the importance to at least question the possibility of a hereditary basis in cases of relatively early-onset malignancy before defining an oncological treatment strategy.
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Affiliation(s)
- Nils W Engel
- Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Simon Schliffke
- Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ulrich Schüller
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Department of Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf, Germany.,Research Institute Children's Cancer Center Hamburg, Hamburg, Germany
| | - Christian Frenzel
- Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Carsten Bokemeyer
- Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Kubisch
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Davor Lessel
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Stolz A, Navarro V, Hayashi PH, Fontana RJ, Barnhart HX, Gu J, Chalasani NP, Vega MM, Bonkovsky HL, Seeff LB, Serrano J, Avula B, Khan I, Cirulli ET, Kleiner DE, Hoofnagle JH, DILIN Investigators.. Severe and protracted cholestasis in 44 young men taking bodybuilding supplements: assessment of genetic, clinical and chemical risk factors. Aliment Pharmacol Ther 2019; 49:1195-1204. [PMID: 30934130 PMCID: PMC6682544 DOI: 10.1111/apt.15211] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/02/2019] [Accepted: 02/10/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Bodybuilding supplements can cause a profound cholestatic syndrome. AIM To describe the drug-Induced liver injury network's experience with liver injury due to bodybuilding supplements. METHODS Liver injury pattern, severity and outcomes, potential genetic associations, and exposure to anabolic steroids by product analysis were analysed in prospectively enrolled subjects with bodybuilding supplement-induced liver injury with causality scores of probable or higher. RESULTS Forty-four males (mean age 33 years) developed liver injury with a median latency of 73 days. Forty-one per cent presented with hepatocellular pattern of liver injury as defined by the R > 5 ([Fold elevation of ALT] ÷ [Fold elevation of Alk Phos] (mean, range = 6.4, 0.5-31.4, n = 42) despite all presenting with clinical features of cholestatic liver injury (100% with jaundice and 84% with pruritus). Liver biopsy (59% of subjects) demonstrated a mild hepatitis and profound cholestasis in most without bile duct injury, loss or fibrosis. Seventy-one per cent were hospitalised, and none died or required liver transplantation. In some, chemical analysis revealed anabolic steroid controlled substances not listed on the label. No enrichment of genetic variants associated with cholestatic syndromes was found, although mutations in ABCB11 (present in up to 20%) were significantly different than in ethnically matched controls. CONCLUSIONS Patients with bodybuilding supplements liver injury uniformly presented with cholestatic injury, which slowly resolved. The ingested products often contained anabolic steroids not identified on the label, and no enrichment in genetic variants was found, indicating a need for additional studies.
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Affiliation(s)
- Andrew Stolz
- University of Southern California, Los Angeles, CA
| | | | | | | | | | | | | | | | | | | | - Jose Serrano
- Liver Diseases Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Bharathi Avula
- National Center for Natural Product Research, School of Pharmacy, University of Mississippi, University, MS
| | - Ikhlas Khan
- National Center for Natural Product Research, School of Pharmacy, University of Mississippi, University, MS
| | | | - David E. Kleiner
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD
| | - Jay H. Hoofnagle
- Liver Diseases Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
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Dietrich CF, Tannapfel A, Jang HJ, Kim TK, Burns PN, Dong Y. Ultrasound Imaging of Hepatocellular Adenoma Using the New Histology Classification. ULTRASOUND IN MEDICINE & BIOLOGY 2019; 45:1-10. [PMID: 30396597 DOI: 10.1016/j.ultrasmedbio.2018.06.015] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 06/20/2018] [Accepted: 06/25/2018] [Indexed: 06/08/2023]
Abstract
Hepatocellular adenoma is a rare benign liver tumor. Predisposing factors include hepatic storage diseases and some genetic conditions. A new histology-based classification has been proposed but to date, the corresponding ultrasound imaging features have not been reported. Here we review the new classification scheme and discuss the corresponding features on contrast-enhanced ultrasound imaging.
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Affiliation(s)
- Christoph F Dietrich
- Medizinische Klinik 2, Caritas-Krankenhaus Bad Mergentheim, Bad Mergentheim, Germany; Ultrasound Department, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | | | - Hyun-Jung Jang
- Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada
| | - Tae Kyoung Kim
- Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada
| | - Peter N Burns
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Yi Dong
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai, China
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Tsilimigras DI, Rahnemai-Azar AA, Ntanasis-Stathopoulos I, Gavriatopoulou M, Moris D, Spartalis E, Cloyd JM, Weber SM, Pawlik TM. Current Approaches in the Management of Hepatic Adenomas. J Gastrointest Surg 2019; 23:199-209. [PMID: 30109469 DOI: 10.1007/s11605-018-3917-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 08/03/2018] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Hepatic adenomas (HAs) are a benign and relatively rare type of liver neoplasms. We review the diagnosis, evaluation, and potential therapeutic management options for patients with HA. METHODS A comprehensive review of the English literature was performed utilizing MEDLINE/PubMed and Web of Science databases with end of search date the 30th April of 2018. In PubMed, the terms "hepatocellular," "hepatic," "liver," and "adenoma," "adenomatosis" were searched in the title and/or abstract. RESULTS Recent advances in molecular classification of HA have determined distinct subtypes with specific clinical, pathological, and imaging characteristics. In general, cessation of exogenous hormonal administration or weight loss may lead to HA regression. Surgical resection, either open or laparoscopic, should be considered in patients with symptoms and risk factors for hemorrhage or malignant transformation. These risk factors include tumor diameter greater than 5 cm, β-catenin activated subtype, and/or male gender. The management of acute hemorrhage should primarily aim at achieving hemodynamic stability via angioembolization followed by elective resection, whereas malignant transformation is treated according to oncologic resection principles. Although pregnancy is one of the known risk factors for tumor growth and associated complications, the presence of an HA per se should not be considered a contradiction to pregnancy. CONCLUSION Future genomic-based multicenter studies are required to provide a strong basis for formulating an evidence-based risk-adapted model that guides individualized management strategies for patients with HA.
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Affiliation(s)
- Diamantis I Tsilimigras
- Laboratory of Experimental Surgery and Surgical Research, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Amir A Rahnemai-Azar
- Department of Surgery, Division of Surgical Oncology, University of Wisconsin Hospital, Madison, WI, USA
| | - Ioannis Ntanasis-Stathopoulos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Alexandra General Hospital, Athens, Greece
| | - Maria Gavriatopoulou
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Alexandra General Hospital, Athens, Greece
| | - Demetrios Moris
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, OH, USA
| | - Eleftherios Spartalis
- Laboratory of Experimental Surgery and Surgical Research, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Jordan M Cloyd
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, OH, USA
| | - Sharon M Weber
- Department of Surgery, Division of Surgical Oncology, University of Wisconsin Hospital, Madison, WI, USA
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, OH, USA.
- Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, Oncology, Health Services Management and Policy, The Ohio State University, Wexner Medical Center, 395 W. 12th Ave., Suite 670, Columbus, OH, USA.
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Pham C, Fong TL, Zhang J, Liu L. Striking Racial/Ethnic Disparities in Liver Cancer Incidence Rates and Temporal Trends in California, 1988-2012. J Natl Cancer Inst 2018; 110:1259-1269. [PMID: 29617913 PMCID: PMC7191878 DOI: 10.1093/jnci/djy051] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 12/26/2017] [Accepted: 02/28/2018] [Indexed: 12/15/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is characterized by disparate risk patterns by race/ethnicity. We examined HCC incidence patterns and temporal trends among detailed racial/ethnic populations, including disaggregated Asian-American subgroups. Methods Using data from the population-based California Cancer Registry, we identified 41 929 invasive HCC cases diagnosed during 1988-2012. Patients were grouped into mutually exclusive racial/ethnic groups of non-Hispanic (NH) white, NH black, Hispanic, and NH Asian/Pacific Islander (API), as well as Asian subgroups of Chinese, Filipino, Japanese, Korean, Vietnamese, Cambodian, Laotian, and South Asian. Age-adjusted and age-specific incidence rates by sex, race/ethnicity, and time period were calculated. The average annual percent change (AAPC) in incidence rates was estimated using joinpoint regression. All estimates were provided with the 95% confidence intervals (CIs). Results Aggregated NH API had higher HCC risk than NH whites, NH blacks, and Hispanics. When disaggregated, Southeast Asians (Vietnamese, Cambodians, and Laotians) had overall HCC incidence rates eight to nine times higher than NH whites and more than twice that of other ethnic Asians. Statistically significant rising temporal trends of HCC were found in NH whites, NH blacks, and Hispanics, especially those older than age 50 years. Overall HCC risk declined in Chinese males (AAPC = -1.3%, 95% CI = -2.0 to -0.6), but rose in Filipino (AAPC = +1.2%, 95% CI = 0.3 to 2.1) and Japanese males (AAPC = +3.0%, 95% CI = 0.4 to 5.6) and Vietnamese (AAPC = +4.5%, 95% CI = 0.7 to 8.5) and Laotian (+3.4%, 95% CI = 0.1 to 6.8) females. Conclusions Our findings provide valuable information for the identification of at-risk ethnic subgroups of Asian Americans while underscoring the importance of disaggregating ethnic populations in cancer research.
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Affiliation(s)
- Christopher Pham
- Doctor of Medicine Program, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Tse-Ling Fong
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Juanjuan Zhang
- Los Angeles Cancer Surveillance Program, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Lihua Liu
- Los Angeles Cancer Surveillance Program, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
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Minguillón J, Surrallés J. Therapeutic research in the crystal chromosome disease Fanconi anemia. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2018; 836:104-108. [PMID: 30389152 DOI: 10.1016/j.mrgentox.2018.05.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/18/2018] [Accepted: 05/07/2018] [Indexed: 01/10/2023]
Abstract
In the last decades there has been a great progress in understanding the pathological and genetic mechanisms involved in Fanconi anemia (FA), a rare disease characterized by chromosome fragility, congenital malformations, bone marrow failure (BMF) and high cancer predisposition. However, these advances have not gone in parallel with the development of medical treatments, with the exception of improved protocols of hematopoietic stem cell transplant (HSCT). BMF and hematological malignancies are the most important and life threatening conditions the patient suffer during the first and second decade of life, respectively, being HSCT the only curative treatment available. Solid tumors are the third hallmark of the disease, usually with poor prognosis as tumor resection is the only therapeutic option given that patients do not tolerate chemotherapy or radiation. With improved HSCT protocols, FA patient survival has increased, leading to a progressively increased number of solid malignancies in adult patients. Therapeutic research is currently focused in targeted therapies for solid tumors as well as in preventive options in the context of drug repurposing. This review summarizes current therapies and drugs used so far in clinical trials to treat Fanconi anemia, as well as the ones used in FA research with potential for future therapeutic opportunities including drugs that suppress chromosome fragility or are expected to delay the onset of BMF and cancer in Fanconi anemia.
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Affiliation(s)
- Jordi Minguillón
- Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Genetics Department and Biomedical Research Institute Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, 08193 Bellaterra, Spain.
| | - Jordi Surrallés
- Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Genetics Department and Biomedical Research Institute Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, 08193 Bellaterra, Spain.
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Hepatocellular adenoma in a woman who was undergoing testosterone treatment for gender identity disorder. Clin J Gastroenterol 2018; 11:401-410. [PMID: 29589251 DOI: 10.1007/s12328-018-0854-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 03/18/2018] [Indexed: 02/06/2023]
Abstract
A 32-year-old Japanese woman was admitted to our hospital for the diagnosis and treatment of multiple liver tumors. She had been receiving 125 mg testosterone enanthate every 2 weeks following female-to-male gender identity disorder (GID) diagnosis at 20 years of age. Ultrasonography, computed tomography, and magnetic resonance imaging showed 11 hepatic nodular tumors with a maximum diameter of 28 mm. Liver tumors with hepatocellular adenoma (HCA) were diagnosed with needle biopsy. Segmentectomy of the left lateral lobe including two lesions, subsegmentectomy of S6 including two lesions, enucleation of each tumor in S5 and S7, and open surgical radiofrequency ablation for each tumor in S4 and S7 were performed. Immunohistochemical specimens showed that the tumor cells were diffusely and strongly positive for glutamine synthetase and that the nuclei were ectopically positive for β-catenin. Thus, the tumors were diagnosed as β-catenin-activated HCA (b-HCA). Transcatheter arterial chemoembolization plus subsequent radiofrequency ablation was performed for the 3 residual lesions in S4 and S8. Although testosterone enanthate was being continued for GID, no recurrence was observed until at least 22 months after the intensive treatments. HCA development in such patients receiving testosterone should be closely monitored using image inspection.
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Abstract
Fanconi anaemia (FA) is a genetic disorder that is characterized by bone marrow failure (BMF), developmental abnormalities and predisposition to cancer. Together with other proteins involved in DNA repair processes and cell division, the FA proteins maintain genome homeostasis, and germline mutation of any one of the genes that encode FA proteins causes FA. Monoallelic inactivation of some FA genes, such as FA complementation group D1 (FANCD1; also known as the breast and ovarian cancer susceptibility gene BRCA2), leads to adult-onset cancer predisposition but does not cause FA, and somatic mutations in FA genes occur in cancers in the general population. Carcinogenesis resulting from a dysregulated FA pathway is multifaceted, as FA proteins monitor multiple complementary genome-surveillance checkpoints throughout interphase, where monoubiquitylation of the FANCD2-FANCI heterodimer by the FA core complex promotes recruitment of DNA repair effectors to chromatin lesions to resolve DNA damage and mitosis. In this Review, we discuss how the FA pathway safeguards genome integrity throughout the cell cycle and show how studies of FA have revealed opportunities to develop rational therapeutics for this genetic disease and for malignancies that acquire somatic mutations within the FA pathway.
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Affiliation(s)
- Grzegorz Nalepa
- Department of Pediatrics, Section of Pediatric Hematology-Oncology, Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W Walnut Street, R4-421, Indianapolis, Indiana 46202, USA
- Riley Hospital for Children at Indiana University Health, 705 Riley Hospital Drive, Room 5900, Indianapolis, Indiana 46202, USA
- Department of Biochemistry, Indiana University School of Medicine
- Department of Medical and Molecular Genetics, Indiana University School of Medicine
| | - D Wade Clapp
- Riley Hospital for Children at Indiana University Health, 705 Riley Hospital Drive, Room 5900, Indianapolis, Indiana 46202, USA
- Department of Biochemistry, Indiana University School of Medicine
- Department of Microbiology and Immunology, Indiana University School of Medicine
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, 46202, USA
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-like Lesions of the Liver. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:780-879. [DOI: 10.1016/b978-0-7020-6697-9.00013-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Kang HJ, Jeong HJ, Kim SW, Yu E, Lee YJ, Kim SY, Kim J. Hepatocellular Carcinoma Arising in a Huge Hepatocellular Adenoma with Bone Marrow Metaplasia. J Pathol Transl Med 2017; 52:226-231. [PMID: 29281780 PMCID: PMC6056361 DOI: 10.4132/jptm.2017.11.12] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 11/12/2017] [Indexed: 01/29/2023] Open
Abstract
Hepatocellular adenoma (HCA) is the most common type of benign liver tumor, and its major complication is malignant transformation to hepatocellular carcinoma (HCC). Here, we report a case of HCC arising in HCA with bone marrow metaplasia in a 24-year-old Korean woman who presented with abdominal discomfort. A huge liver mass was found on abdominal ultrasonography. She underwent surgical hepatic resection, and the resected specimen was entirely involved by a 20-cm-sized tumor. Histological review revealed a well differentiated HCC arising from inflammatory HCA with β-catenin nuclear positivity and bone marrow metaplasia that contained hematopoietic cells. This case was unique because malignant transformation, inflammatory type HCA, β-catenin nuclear staining, and bone marrow metaplasia were simultaneously observed. Additionally, it should be noted that a large HCA with β-catenin activation can undergo malignant transformation and should be surgically resected in a timely manner.
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Affiliation(s)
- Hyo Jeong Kang
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hui Jeong Jeong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - So-Woon Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Eunsil Yu
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Department of Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young-Joo Lee
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - So Yeon Kim
- Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jihun Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Liu D, Liu P, Cao L, Zhang Q, Chen Y. Screening the key genes of hepatocellular adenoma via microarray analysis of DNA expression and methylation profiles. Oncol Lett 2017; 14:3975-3980. [PMID: 28943905 PMCID: PMC5605960 DOI: 10.3892/ol.2017.6673] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 05/23/2017] [Indexed: 01/30/2023] Open
Abstract
The aim of the present study was to identify the biomarkers involved in the development of hepatocellular adenoma (HCA) through integrated analysis of gene expression and methylation microarray. The microarray dataset GSE7473, containing HNF1α-mutated HCA and their corresponding non-tumor livers, 5 HNF1α-mutated HCA and 4 non-related non-tumor livers, was downloaded from the Gene Expression Omnibus (GEO) database. The DNA methylation profile GSE43091, consisting of 50 HCA and 4 normal liver tissues, was also downloaded from the GEO database. Differentially expressed genes (DEGs) were identified by the limma package of R. A t-test was conducted on the differentially methylated sites. Functional enrichment analysis of DEGs was performed through the Database for Annotation, Visualization and Integrated Analysis. The genes corresponding to the differentially methylated sites were obtained by the annotation files of methylation chip platform. A total of 182 DEGs and 3,902 differentially methylated sites were identified in HCA. In addition, 238 enriched GO terms, including organic acid metabolic process and carboxylic acid metabolic process, and 14 KEGG pathways, including chemical carcinogenesis, were identified. Furthermore, 12 DEGs were identified to contain differentially methylated sites, among which, 8 overlapped genes, including pregnancy zone protein and solute carrier family 22 member 1 (SLC22A1), exhibited inverse associations between gene expression levels and DNA methylation levels. The DNA methylation levels may be potential targets of HCA. The present study revealed that the 8 overlapped genes, including annexin A2, chitinase 3-like 1, fibroblast growth factor receptor 4, mal, T-cell differentiation protein like, palladin, cytoskeletal associated protein, plasmalemma vesicle associated protein and SLC22A1, may be potential therapeutic targets of HCA.
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Affiliation(s)
- Dan Liu
- Department of Ultrasonic Imaging, Zhuhai People's Hospital, Zhuhai, Guangdong 519000, P.R. China
| | - Pengfei Liu
- Department of Lymphoma, Sino-US Center of Lymphoma and Leukemia, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, P.R. China
| | - Liye Cao
- Department of Ultrasonic Medicine, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| | - Quan Zhang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| | - Yaqing Chen
- Department of VIP Ward, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
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Fabresse N, Grassin-Delyle S, Etting I, Alvarez JC. Detection and quantification of 12 anabolic steroids and analogs in human whole blood and 20 in hair using LC-HRMS/MS: application to real cases. Int J Legal Med 2017; 131:989-999. [DOI: 10.1007/s00414-017-1552-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Accepted: 01/31/2017] [Indexed: 01/31/2023]
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Xue Y, Farris AB, Quigley B, Krasinskas A. The Impact of New Technologic and Molecular Advances in the Daily Practice of Gastrointestinal and Hepatobiliary Pathology. Arch Pathol Lab Med 2017; 141:517-527. [PMID: 28157407 DOI: 10.5858/arpa.2016-0261-sa] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The practice of anatomic pathology, and of gastrointestinal pathology in particular, has been dramatically transformed in the past decade. In addition to the multitude of diseases, syndromes, and clinical entities encountered in daily clinical practice, the increasing integration of new technologic and molecular advances into the field of gastroenterology is occurring at a fast pace. Application of these advances has challenged pathologists to correlate newer methodologies with existing morphologic criteria, which in many instances still provide the gold standard for diagnosis. This review describes the impact of new technologic and molecular advances on the daily practice of gastrointestinal and hepatobiliary pathology. We discuss new drugs that can affect the gastrointestinal tract and liver, new endoluminal techniques, new molecular tests that are often performed reflexively, new imaging techniques for evaluating hepatocellular carcinoma, and modified approaches to the gross and histologic assessment of tissues that have been exposed to neoadjuvant therapies.
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Affiliation(s)
| | | | | | - Alyssa Krasinskas
- From the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia
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