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Pio L, O'Neill AF, Woodley H, Murphy AJ, Tiao G, Franchi-Abella S, Fresneau B, Watanabe K, Alaggio R, Lopez-Terrada D, Hiyama E, Branchereau S. Hepatoblastoma. Nat Rev Dis Primers 2025; 11:36. [PMID: 40404742 DOI: 10.1038/s41572-025-00620-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/17/2025] [Indexed: 05/24/2025]
Abstract
Hepatoblastoma is the most common primary liver cancer in children, with an incidence of approximately 1.5 cases per million children per year. Most cases are sporadic, typically presenting at a median age of 18 months, with only 5% occurring after 4 years of age. Clinical presentation often includes an abdominal mass and, less commonly, abdominal pain, weight loss, jaundice and precocious puberty. Low birth weight is a significant risk factor, along with genetic conditions such as Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome, familial adenomatous polyposis and trisomy 18. Screening protocols for hepatoblastoma are recommended for children with predisposing conditions. Medical imaging is crucial for hepatoblastoma diagnosis and staging, with abdominal ultrasonography being the initial modality of choice, followed by abdominal contrast MRI for detailed evaluation and monitoring. Chest computer tomography is indicated to evaluate potential lung metastases. The Pretreatment Extent of Disease (PRETEXT) system is employed for hepatoblastoma staging and for guiding treatment strategies such as surgical resection and chemotherapy. Patients with advanced hepatoblastoma may require liver transplantation. Advancements in surgery and chemotherapy have improved survival rates, with 5-year survival rates exceeding 80-90% in localized disease. However, challenges remain in treating individuals with high-risk and metastatic hepatoblastoma. Ongoing research into treatment stratification, the introduction of novel therapies, including targeted and immune therapies, and the application of otoprotectants are essential to address refractory or recurrent hepatoblastoma and to increase the overall survival of patients. Long-term quality of life and the management of treatment-related sequelae are becoming increasingly important as survival rates improve.
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Affiliation(s)
- Luca Pio
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA.
- Paediatric Surgery Unit, Université Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin-Bicêtre, France.
| | - Allison F O'Neill
- Department of Paediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA
| | - Helen Woodley
- Department of Paediatric Radiology, Leeds Children's Hospital, Leeds, UK
| | - Andrew J Murphy
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Gregory Tiao
- Division of General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Stefanie Franchi-Abella
- Department of Paediatric Radiology, Université Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin-Bicêtre, France
| | - Brice Fresneau
- Department of Children and Adolescents Oncology, Gustave Roussy, University Paris Saclay and Radiation Epidemiology Team, CESO, Inserm U1018, Villejuif, France
| | - Kenichiro Watanabe
- Department of Hematology and Oncology, Shizuoka Children's Hospital, Shizuoka, Japan
| | - Rita Alaggio
- Pathology Department, Ospedale Paediatrico Bambino Gesù IRCCS, Rome, Italy
| | - Dolores Lopez-Terrada
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA
| | - Eiso Hiyama
- Department of Biomedical Science, Natural Science Center for Basic Research and Development (N-BARD), Hiroshima University, Hiroshima, Japan
| | - Sophie Branchereau
- Paediatric Surgery Unit, Université Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin-Bicêtre, France
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Fan L, Na J, Shi T, Liao Y. Hepatoblastoma: From Molecular Mechanisms to Therapeutic Strategies. Curr Oncol 2025; 32:149. [PMID: 40136353 PMCID: PMC11941340 DOI: 10.3390/curroncol32030149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 02/23/2025] [Accepted: 03/02/2025] [Indexed: 03/27/2025] Open
Abstract
Hepatoblastoma (HB) is the most common malignant liver tumor in children under five years of age. Although globally rare, it accounts for a large proportion of liver cancer in children and has poor survival rates in high-risk and metastatic cases. This review discusses the molecular mechanisms, diagnostic methods, and therapeutic strategies of HB. Mutations in the CTNNB1 gene and the activation of the Wnt/β-catenin pathway are essential genetic factors. Furthermore, genetic syndromes like Beckwith-Wiedemann syndrome (BWS) and Familial Adenomatous Polyposis (FAP) considerably heighten the risk of associated conditions. Additionally, epigenetic mechanisms, such as DNA methylation and the influence of non-coding RNAs (ncRNAs), are pivotal drivers of tumor development. Diagnostics include serum biomarkers, immunohistochemistry (IHC), and imaging techniques. Standard treatments are chemotherapy, surgical resection, and liver transplantation (LT). Emerging therapies like immunotherapy and targeted treatments offer hope against chemotherapy resistance. Future research will prioritize personalized medicine, novel biomarkers, and molecular-targeted therapies to improve survival outcomes.
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Affiliation(s)
- Ling Fan
- State Key Laboratory of Targeting Oncology, Guangxi Medical University, Nanning 530021, China; (L.F.); (J.N.)
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Medical University, Nanning 530021, China
- Guangxi Key Laboratory of Bio-Targeting Theranostics, Guangxi Medical University, Nanning 530021, China
- Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning 530021, China
- Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China
| | - Jintong Na
- State Key Laboratory of Targeting Oncology, Guangxi Medical University, Nanning 530021, China; (L.F.); (J.N.)
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Medical University, Nanning 530021, China
- Guangxi Key Laboratory of Bio-Targeting Theranostics, Guangxi Medical University, Nanning 530021, China
- Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning 530021, China
- Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China
| | - Tieliu Shi
- State Key Laboratory of Targeting Oncology, Guangxi Medical University, Nanning 530021, China; (L.F.); (J.N.)
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Medical University, Nanning 530021, China
- Guangxi Key Laboratory of Bio-Targeting Theranostics, Guangxi Medical University, Nanning 530021, China
- Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning 530021, China
- Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China
- Center for Bioinformatics and Computational Biology, Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
- Key Laboratory of Advanced Theory and Application in Statistics and Data Science (MOE), School of Statistics, East China Normal University, Shanghai 200062, China
| | - Yuan Liao
- State Key Laboratory of Targeting Oncology, Guangxi Medical University, Nanning 530021, China; (L.F.); (J.N.)
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Medical University, Nanning 530021, China
- Guangxi Key Laboratory of Bio-Targeting Theranostics, Guangxi Medical University, Nanning 530021, China
- Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning 530021, China
- Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China
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All Mahmud A, Hossain Z, Khan MA, Shahinoor AM, Dilshad Munmun UH, Methila MK, Zafar SS, Islam T. Early Surgical Outcome of Hepatoblastoma in Children Receiving Chemotherapy After Hepatic Resection. Cureus 2025; 17:e80334. [PMID: 40206916 PMCID: PMC11980305 DOI: 10.7759/cureus.80334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/10/2025] [Indexed: 04/11/2025] Open
Abstract
OBJECTIVE The aim of this study was to evaluate surgical outcomes in children with hepatoblastoma who underwent hepatic resection after receiving neoadjuvant chemotherapy. METHODOLOGY A prospective observational longitudinal study was conducted from February 2019 to July 2020 in the Department of Pediatric Surgery at Bangabandhu Sheikh Mujib Medical University, Bangladesh. A total of 13 children diagnosed with hepatoblastoma and classified as PRETEXT (Pre-Treatment Extent of Disease) stages I to III were included. Detailed medical histories were recorded, and diagnoses were confirmed through histopathological analysis. Preoperative evaluations included liver function tests (LFTs), serum alpha-fetoprotein (AFP) levels, and imaging for tumor staging and liver volume. Postoperative assessments were conducted at one, three, and six months to monitor changes in serum AFP levels, LFTs, liver volume, and hepatic echotexture. The type of hepatic resection performed and any complications encountered were also documented. RESULTS Among the 13 patients, the majority were male, with a male-to-female ratio of 12:1. The average age at diagnosis was 4.44 years, with most patients under three years old. Pathological analysis revealed epithelial tumors in 38.45% of cases, fetal-type tumors in 46.15%, and mixed tumors in 15.4%. PRETEXT stage III was the most common (53.85%), and 61.54% of patients underwent major hepatic resections. Postoperative serum AFP levels showed a significant decline, reflecting successful tumor resection and improvements in LFTs. Improvements in LFTs, including key enzymes like ALT and AST, were observed. A marked increase in hepatic regeneration was observed within six months, with no local recurrences recorded. CONCLUSIONS This study highlights the effectiveness of combining hepatic resection with neoadjuvant chemotherapy in treating pediatric hepatoblastoma. A significant decline in serum AFP levels after surgery reflects the success of tumor removal, while improvements in LFTs underscore the recovery of hepatic health. Furthermore, the observed increase in hepatic regeneration within six months demonstrates the liver's remarkable ability to recover and sustain long-term function. These findings emphasize the importance of early diagnosis, precise surgical techniques, and individualized treatment planning in improving outcomes for pediatric hepatoblastoma.
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Affiliation(s)
- Abdullah All Mahmud
- Department of Pediatric Surgery, Shaheed Suhrawardy Medical College and Hospital, Dhaka, BGD
- Department of Pediatric Surgery, Bangabandhu Sheikh Mujib Medical University, Dhaka, BGD
| | - Zahid Hossain
- Department of Pediatric Surgery, Bangabandhu Sheikh Mujib Medical University, Dhaka, BGD
| | - Mahfuz Alam Khan
- Department of Pediatric Surgery, Mymensingh Medical College Hospital, Mymensingh, BGD
- Department of Pediatric Surgery, Bangabandhu Sheikh Mujib Medical University, Dhaka, BGD
| | - A M Shahinoor
- Department of Pediatric Surgery, Bangabandhu Sheikh Mujib Medical University, Dhaka, BGD
| | | | - Meherun Khan Methila
- Department of Pediatric Surgery, Rangpur Medical College and Hospital, Rangpur, BGD
| | - Syeda Sushmita Zafar
- Department of Community Medicine, Saic College of Medical Science and Technology, Dhaka, BGD
| | - Tanjirul Islam
- Department of Pediatric Surgery, Bangabandhu Sheikh Mujib Medical University, Dhaka, BGD
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Hiyama E, Hishiki T, Yoshimura K, Krailo M, Maibach R, Haeberle B, Rangaswami A, Lopez-Terrada D, Malogolowkin MH, Ansari M, Alaggio R, O’Neill AF, Trobaugh-Lotrario AD, Watanabe K, Schmid I, Ranganathan S, Tanaka Y, Inoue T, Piao J, Lin J, Czauderna P, Meyers RL, Aronson DC. Upfront or delayed surgery in resectable hepatoblastoma: analysis from the children's hepatic tumors international collaboration database. EClinicalMedicine 2024; 76:102811. [PMID: 39309724 PMCID: PMC11414700 DOI: 10.1016/j.eclinm.2024.102811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 08/14/2024] [Accepted: 08/19/2024] [Indexed: 09/25/2024] Open
Abstract
Background In the treatment of resectable hepatoblastoma (HB), it has not been established whether upfront surgery (UF) at diagnosis or neoadjuvant chemotherapy and delayed surgery (DL) is preferred. We compared patients with localized HB who underwent either UF, or DL after neoadjuvant chemotherapy in the Children's Hepatic tumors International Collaboration (CHIC) database of 1605 cases enrolled in eight multicenter hepatoblastoma trials between 1988 and 2010. Methods Among the 512 resectable HB patients who had PRETEXT (PRETreament EXTent of disease) I or II unruptured tumors at diagnosis without extrahepatic invasion, distant metastases, or massive vascular invasion, 172 underwent UF and 340 underwent DL. The primary outcomes were event-free and overall survivals after start of treatment in these two groups. Survival analysis was performed using the Kaplan-Maier analysis with long-rank tests and multivariable Cox regression models. Findings Complete resection rates were comparable (93.6% in UF and 89.7% in DL). The total cycles of chemotherapy of DL (median:6) were significantly more than those of UF (median:4) (P < 0.01). The 5-year event-free survival (EFS) was 90.6% and 86.6% (P = 0.89) in the UF and DL cohorts, respectively. The surgical complications, recurrence rates, and late complications were not significantly different between the cohorts but the EFS rates of DL patients with a low alpha-fetoprotein (AFP) level (100-999 ng/mL) or older age at diagnosis (≥3 years old) were significantly worse than others. Interpretation The outcomes, surgical resectability, and complications were not significantly different between the UF and DL groups. Eligible patients with a low AFP level (<1000 ng/mL) or older age (≥3 years old) showed better outcomes in the UF group and might be considered for initial resection. Funding European Network for Cancer Research in Children and Adolescents, funded through the Framework Program 7 of the European Commission; Children's Oncology Group Cure Search grant contributed by the Hepatoblastoma Foundation; Practical Research for Innovative Cancer Control and Project Promoting Clinical Trials for Development of New Drugs and Medical Devices, Japan Agency for Medical Research and Development; Japan Society for the Promotion of Science; and Swiss Cancer Research grant.
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Affiliation(s)
- Eiso Hiyama
- Natural Science for Basic Research and Development, Department of Pediatric Surgery, Hiroshima University Hospital, Hiroshima University, Hiroshima, Japan
| | - Tomoro Hishiki
- Department of Pediatric Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Kenichi Yoshimura
- Department of Biostatistics and Health Data Science, Nagoya City University, Japan
| | - Mark Krailo
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
| | | | - Beate Haeberle
- Department of Pediatric Surgery, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Germany
| | - Arun Rangaswami
- Division of Pediatric Hematology and Oncology, University of California San Francisco, San Francisco, CA, USA
| | - Dolores Lopez-Terrada
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA
| | - Marcio H. Malogolowkin
- Division of Pediatric Hematology Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA
| | - Marc Ansari
- Cansearch Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, Department of Pediatrics, Gynecology and Obstetrics, University of Geneva, Geneva, Switzerland
- Division of Pediatric Oncology and Hematology, Department of Women, Child and Adolescent, University Geneva Hospitals, Geneva, Switzerland
| | - Rita Alaggio
- Pathology Unit, IRCCS Ospedale Pediatrico Bambino Gesu Pediatric Hospital, Roma, Italy
- Department of Medical and Surgical Biotechnology Sciences, Sapienza University, Roma, Italy
| | - Allison F. O’Neill
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA
| | | | - Kenichiro Watanabe
- Department of Hematology and Oncology, Shizuoka Children’s Hospital, Shizuoka, Japan
| | - Irene Schmid
- Department of Pediatric Hematology and Oncology, Dr. von Hauner Children`s Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Sarangarajan Ranganathan
- Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Yukichi Tanaka
- Department of Pathology, Kanagawa Children’s Medical Center, Yokohama, Japan
| | - Takeshi Inoue
- Department of Pathology, Osaka City General Hospital, Osaka, Japan
| | - Jin Piao
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jason Lin
- Division of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Piotr Czauderna
- Department of Surgery and Urology, for Children and Adolescents, Medical University of Gdansk, Poland
| | - Rebecka L. Meyers
- Division of Pediatric Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Daniel C. Aronson
- Department of Pediatric Surgery, University Children’s Hospital Zurich, Zurich, Switzerland
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Gao H, Xie C, Wang J, Ma J, Liu S, Xie L, Zheng Y, Dong R, Wang S, Fang Y, Wu Y, Zhang X, Lu X, Li Y, Li W, Pan Q, Xu M, Gu S. PIVKA-II combined with alpha-fetoprotein for the diagnostic value of hepatic tumors in children: a multicenter, prospective observational study. Hepatol Int 2024; 18:1326-1335. [PMID: 38622445 PMCID: PMC11297896 DOI: 10.1007/s12072-024-10668-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 07/09/2022] [Indexed: 04/17/2024]
Abstract
BACKGROUND To investigate whether protein induced by vitamin K antagonist-II (PIVKA-II) combined with alpha-fetoprotein (AFP) can improve the diagnostic and differential diagnostic accuracy of childhood hepatic tumors. METHODS A multi-center prospective observational study was performed at nine regional institutions around China. Children with hepatic mass (Group T) were divided into hepatoblastoma group (Group THB) and hemangioendothelioma group (Group THE), children with extrahepatic abdominal mass (Group C). Peripheral blood was collected from each patient prior to surgery or chemotherapy. The area under the curve (AUROC) was used to evaluate the diagnostic efficiency of PIVKA-II and the combined tumor markers with AFP. RESULTS The mean levels of PIVKA-II and AFP were both significantly higher in Group T than Group C (p = 0.001, p < 0.001), in Group THB than Group THE (p = 0.018, p = 0.013) and in advanced HB than non-advanced HB (p = 0.001, p = 0.021). For the diagnosis of childhood hepatic tumors, AUROC of PIVKA-II (cut-off value 32.6 mAU/mL) and AFP (cut-off value 120 ng/mL) was 0.867 and 0.857. The differential diagnostic value of PIVKA-II and AFP in hepatoblastoma from hemangioendothelioma was further assessed, AUROC of PIVKA-II (cut-off value 47.1mAU/mL) and AFP (cut-off value 560 ng/mL) was 0.876 and 0.743. The combined markers showed higher AUROC (0.891, 0.895 respectively) than PIVKA-II or AFP alone. CONCLUSIONS The serum level of PIVKA-II was significantly higher in children with hepatic tumors, especially those with malignant tumors. The combination of PIVKA-II with AFP further increased the diagnostic performance. TRIAL REGISTRATION Clinical Trials, NCT03645655. Registered 20 August 2018, https://www. CLINICALTRIALS gov/ct2/show/NCT03645655 .
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Affiliation(s)
- Hongxiang Gao
- Department of Pediatric General Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Dongfang Road No. 1678, Pudong New District, Shanghai, 200127, China
| | - Chenjie Xie
- Department of Pediatric General Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Dongfang Road No. 1678, Pudong New District, Shanghai, 200127, China
| | - Jing Wang
- Department of Pediatric General Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Dongfang Road No. 1678, Pudong New District, Shanghai, 200127, China
| | - Ji Ma
- Department of Laboratory Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Shijian Liu
- Child Health Advocacy Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Li Xie
- Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yijie Zheng
- Department of Medical Affairs, Wuxidiagnotics, Shanghai, 200131, China
| | - Rui Dong
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Shan Wang
- Department of Pediatric Surgical Oncology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Yongjun Fang
- Department of Hematology and Oncology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
| | - Yurui Wu
- Department of Minimally Invasive Surgery, Qilu Children's Hospital of Shandong University, Jinan, 250022, Shandong, China
| | - Xianwei Zhang
- Department of Oncology Surgery, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Xianying Lu
- Department of Pediatric Surgery, Anhui Provincial Children's Hospital, Hefei, 230051, China
| | - Yang Li
- Department of Pediatric Hematology/Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 519000, China
| | - Weisong Li
- Department of General Surgery, Pediatric Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Qiuhui Pan
- Department of Laboratory Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Min Xu
- Department of Pediatric General Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Dongfang Road No. 1678, Pudong New District, Shanghai, 200127, China.
| | - Song Gu
- Department of Pediatric General Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Dongfang Road No. 1678, Pudong New District, Shanghai, 200127, China.
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Wang S, Fu S, Li R, Guo Z, Wang Y, Sun W, Sun D. Construction and validation of nomogram prognostic model for predicting survival in hepatoblastoma patients: a population-based study. Updates Surg 2024; 76:1223-1234. [PMID: 38795309 DOI: 10.1007/s13304-024-01814-6] [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: 05/24/2023] [Accepted: 03/04/2024] [Indexed: 05/27/2024]
Abstract
For patients with hepatoblastoma (HB), current staging system is not accurate in predicting survival outcomes. The aim of this study was to develop two accurate survival prediction models to guide clinical decision making. A retrospective analysis of 424 HB patients was performed from 2004 to 2015 using the Surveillance, Epidemiology and End Results (SEER) database. Univariate and multivariate Cox regression analysis was used to screen for variables. The identified variables were used to build survival prediction model. The performance of the nomogram models was assessed based on the concordance index (C-index), calibration plot, and receiver operating characteristic (ROC) curve. The Cox regression analysis identified six variables affecting overall survival (OS) in HB patients, including race, tumor size, lymph node involvement, distant metastases, surgery and chemotherapy. And the Cox regression analysis identified five variables including race, lymph node involvement, distant metastases, surgery, and chemotherapy that affect cancer-specific survival (CCS) in HB patients. In the training cohort, the C-index of the nomogram in predicting the OS was 0.791 [95% confidence intervals (95% CI) 0.717-0.865], CSS was 0.805(95% CI 0.728-0.882). In the validation cohort, the C-index of the nomogram in predicting the OS was 0.712 (95% CI 0.511-0.913), the CSS was 0.751 (95% CI 0.566-0.936). In the training cohort, the area under the receiver operator characteristics curve (AUC) values of the nomogram in prediction of the 1-, 3-, and 5-year OS were 0.842 (95% CI 0.739-0.944), 0.759 (95% CI 0.670-0.849), and 0.770 (95% CI 0.686-0.852), respectively. In the validation cohort, the AUC values for prediction of the 1-, 3-, and 5-year OS were 0.920 (95% CI 0.806-1.034), 0.863 (95% CI 0.750-0.976), and 0.844 (95% CI 0.721-0.967), respectively. Two nomogram models were developed and validated in this study which provided accurate prediction of the OS and CSS in HB patients. The constructed models can be used for predicting survival outcomes and guide treatment for HB patients.
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Affiliation(s)
- Song Wang
- Department of Pediatric Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Siqi Fu
- Department of Pediatric Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Rui Li
- Department of Pediatric Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Zheng Guo
- Department of Pediatric Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Yuchao Wang
- Department of Pediatric Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Wei Sun
- Department of Pediatric Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Daqing Sun
- Department of Pediatric Surgery, Tianjin Medical University General Hospital, Tianjin, China.
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7
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Garg HK, Shashi KK, Fisher P, Winant AJ, Hull NC, Lee EY. Pediatric Upper Abdominal Masses: Current Practical Imaging Assessment. Semin Roentgenol 2024; 59:299-311. [PMID: 38997183 DOI: 10.1053/j.ro.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 02/29/2024] [Accepted: 03/04/2024] [Indexed: 07/14/2024]
Affiliation(s)
- Harsha K Garg
- Department of Diagnostic, Molecular and Interventional Radiology and Pediatrics, Kravis Children's Hospital, Icahn School of Medicine at The Mount Sinai Hospital, New York, NY.
| | - Kumar K Shashi
- Department of Radiology, Arkansas Children's Hospital, Little Rock, AR
| | - Paul Fisher
- Department of Diagnostic, Molecular and Interventional Radiology and Pediatrics, Kravis Children's Hospital, Icahn School of Medicine at The Mount Sinai Hospital, New York, NY
| | - Abbey J Winant
- Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA
| | - Nathan C Hull
- Department of Radiology, Division of Pediatric Radiology, Mayo Clinic, Rochester, MN
| | - Edward Y Lee
- Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA
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8
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Yang Y, Wang H, Si J, Zhang L, Ding H, Wang F, He L, Chen X. Predicting response of hepatoblastoma primary lesions to neoadjuvant chemotherapy through contrast-enhanced computed tomography radiomics. J Cancer Res Clin Oncol 2024; 150:223. [PMID: 38691204 PMCID: PMC11063102 DOI: 10.1007/s00432-024-05746-x] [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: 02/26/2024] [Accepted: 04/08/2024] [Indexed: 05/03/2024]
Abstract
OBJECTIVE To investigate the clinical value of contrast-enhanced computed tomography (CECT) radiomics for predicting the response of primary lesions to neoadjuvant chemotherapy in hepatoblastoma. METHODS Clinical and CECT imaging data were retrospectively collected from 116 children with hepatoblastoma who received neoadjuvant chemotherapy. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). Subsequently, they were randomly stratified into a training cohort and a test cohort in a 7:3 ratio. The clinical model was constructed using univariate and multivariate logistic regression, while the radiomics model was developed based on selected radiomics features employing the support vector machine algorithm. The combined clinical-radiomics model incorporated both clinical and radiomics features. RESULTS The area under the curve (AUC) for the clinical, radiomics, and combined models was 0.704 (95% CI: 0.563-0.845), 0.830 (95% CI: 0.704-0.959), and 0.874 (95% CI: 0.768-0.981) in the training cohort, respectively. In the validation cohort, the combined model achieved the highest mean AUC of 0.830 (95% CI 0.616-0.999), with a sensitivity, specificity, accuracy, precision, and f1 score of 72.0%, 81.1%, 78.5%, 57.2%, and 63.5%, respectively. CONCLUSION CECT radiomics has the potential to predict primary lesion response to neoadjuvant chemotherapy in hepatoblastoma.
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Affiliation(s)
- Yanlin Yang
- Department of Radiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China
| | - Haoru Wang
- Department of Radiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China
| | - Jiajun Si
- Department of Radiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China
| | - Li Zhang
- Department of Radiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China
| | - Hao Ding
- Department of Radiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China
| | - Fang Wang
- Department of Research and Development, Shanghai United Imaging Intelligence Co., Ltd, Shanghai, China
| | - Ling He
- Department of Radiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China.
| | - Xin Chen
- Department of Radiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China.
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9
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Pire A, Hirsch TZ, Morcrette G, Imbeaud S, Gupta B, Pilet J, Cornet M, Fabre M, Guettier C, Branchereau S, Brugières L, Guerin F, Laithier V, Coze C, Nagae G, Hiyama E, Laurent-Puig P, Rebouissou S, Sarnacki S, Chardot C, Capito C, Faure-Conter C, Aerts I, Taque S, Fresneau B, Zucman-Rossi J. Mutational signature, cancer driver genes mutations and transcriptomic subgroups predict hepatoblastoma survival. Eur J Cancer 2024; 200:113583. [PMID: 38330765 DOI: 10.1016/j.ejca.2024.113583] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 01/17/2024] [Accepted: 01/23/2024] [Indexed: 02/10/2024]
Abstract
BACKGROUND Hepatoblastoma is the most frequent pediatric liver cancer. The current treatments lead to 80% of survival rate at 5 years. In this study, we evaluated the clinical relevance of molecular features to identify patients at risk of chemoresistance, relapse and death of disease. METHODS All the clinical data of 86 children with hepatoblastoma were retrospectively collected. Pathological slides were reviewed, tumor DNA sequencing (by whole exome, whole genome or target) and transcriptomic profiling with RNAseq or 300-genes panel were performed. Associations between the clinical, pathological, mutational and transcriptomic data were investigated. RESULTS High-risk patients represented 44% of our series and the median age at diagnosis was 21.9 months (range: 0-208). Alterations of the WNT/ß-catenin pathway and of the 11p15.5 imprinted locus were identified in 98% and 74% of the tumors, respectively. Other cancer driver genes mutations were only found in less than 11% of tumors. After neoadjuvant chemotherapy, disease-specific survival and poor response to neoadjuvant chemotherapy were associated with 'Liver Progenitor' (p = 0.00049, p < 0.0001) and 'Immune Cold' (p = 0.0011, p < 0.0001) transcriptomic tumor subtypes, SBS35 cisplatin mutational signature (p = 0.018, p = 0.001), mutations in rare cancer driver genes (p = 0.0039, p = 0.0017) and embryonal predominant histological type (p = 0.0013, p = 0.0077), respectively. Integration of the clinical and molecular features revealed a cluster of molecular markers associated with resistance to chemotherapy and survival, enlightening transcriptomic 'Immune Cold' and Liver Progenitor' as a predictor of survival independent of the clinical features. CONCLUSIONS Response to neoadjuvant chemotherapy and survival in children treated for hepatoblastoma are associated with genomic and pathological features independently of the clinical features.
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Affiliation(s)
- Aurore Pire
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006 Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, Labex Onco-Immunology, Institute du Cancer Paris CARPEM, AP-HP, F-75015 Paris, France; Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Bruxelles, Belgium
| | - Theo Z Hirsch
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006 Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, Labex Onco-Immunology, Institute du Cancer Paris CARPEM, AP-HP, F-75015 Paris, France
| | - Guillaume Morcrette
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006 Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, Labex Onco-Immunology, Institute du Cancer Paris CARPEM, AP-HP, F-75015 Paris, France; Pathology Department, AP-HP Necker Enfants Malades Hospital, F-75015 Paris, France
| | - Sandrine Imbeaud
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006 Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, Labex Onco-Immunology, Institute du Cancer Paris CARPEM, AP-HP, F-75015 Paris, France
| | - Barkha Gupta
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006 Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, Labex Onco-Immunology, Institute du Cancer Paris CARPEM, AP-HP, F-75015 Paris, France
| | - Jill Pilet
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006 Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, Labex Onco-Immunology, Institute du Cancer Paris CARPEM, AP-HP, F-75015 Paris, France
| | - Marianna Cornet
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006 Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, Labex Onco-Immunology, Institute du Cancer Paris CARPEM, AP-HP, F-75015 Paris, France
| | - Monique Fabre
- Pathology Department, AP-HP Necker Enfants Malades Hospital, F-75015 Paris, France
| | - Catherine Guettier
- Department of Pathology, AP-HP Bicêtre Hospital, F-94270 Le Kremlin-Bicêtre, France
| | - Sophie Branchereau
- Department of Pediatric Surgery, AP-HP Bicêtre Hospital, F-94270 Le Kremlin-Bicêtre, France
| | - Laurence Brugières
- Gustave Roussy, Université Paris-Saclay, Department of Children and Adolescents Oncology, Villejuif F-94805, France
| | - Florent Guerin
- Department of Pediatric Surgery, AP-HP Bicêtre Hospital, F-94270 Le Kremlin-Bicêtre, France
| | | | - Carole Coze
- Department of Pediatric and Oncology, Hopital de La Timone, Aix Marseille University, F-13005 Marseille, France
| | - Genta Nagae
- Genome Science Laboratory, Research Center for Advanced Science and Technology (RCAST), the University of Tokyo, Tokyo, Japan
| | - Eiso Hiyama
- Department of Pediatric Surgery, Hiroshima University Hospital, Hiroshima, Japan; Department of Biomedical Science, Natural Science Center for Basic Research and Development (N-BARD), Hiroshima University, Hiroshima, Japan
| | - Pierre Laurent-Puig
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006 Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, Labex Onco-Immunology, Institute du Cancer Paris CARPEM, AP-HP, F-75015 Paris, France
| | - Sandra Rebouissou
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006 Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, Labex Onco-Immunology, Institute du Cancer Paris CARPEM, AP-HP, F-75015 Paris, France
| | - Sabine Sarnacki
- Department of Pediatric Surgery, AP-HP Necker Enfants Malades Hospital, F-75015 Paris, France
| | - Christophe Chardot
- Department of Pediatric Surgery, AP-HP Necker Enfants Malades Hospital, F-75015 Paris, France
| | - Carmen Capito
- Department of Pediatric Surgery, AP-HP Necker Enfants Malades Hospital, F-75015 Paris, France
| | - Cécile Faure-Conter
- Institut d'hématologie et d'oncologie pédiatrique de Lyon, F-69008 Lyon, France
| | - Isabelle Aerts
- Institut Curie, Oncology Center SIREDO, F-75005 Paris, France
| | - Sophie Taque
- Pediatric Department hemato-oncology, CHU Rennes, F-35033 Rennes, France
| | - Brice Fresneau
- Gustave Roussy, Université Paris-Saclay, Department of Children and Adolescents Oncology, Villejuif F-94805, France; Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, Cancer and Radiation Team, F-94805 Villejuif, France
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006 Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, Labex Onco-Immunology, Institute du Cancer Paris CARPEM, AP-HP, F-75015 Paris, France; AP-HP, Department of Oncology, Hopital Européen Georges Pompidou, F-75015 Paris, France.
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10
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Ziogas IA, Roach JP, Acker SN, Corkum KS, Diaz-Miron JL, Kulungowski AM, Gosain A, Hills-Dunlap JL. Association of Sociodemographic Factors with Surgical Management of Hepatoblastoma and Hepatocellular Carcinoma in Children. J Pediatr 2024; 269:113963. [PMID: 38369237 DOI: 10.1016/j.jpeds.2024.113963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 01/12/2024] [Accepted: 02/13/2024] [Indexed: 02/20/2024]
Abstract
OBJECTIVE To evaluate for disparities in surgical care among US children with hepatoblastoma (HB) and hepatocellular carcinoma (HCC). STUDY DESIGN In this retrospective National Cancer Database study (2004-2015), children aged <18 years with HB or HCC were included. Multivariable mixed-effects logistic regression was used to evaluate the association of sociodemographic factors (age, sex, race and ethnicity, insurance status, income, proximity to treating hospital) with the odds of undergoing surgical treatment after adjusting for disease-related factors (tumor size, metastasis, comorbidities) and hospital-level effects. Subgroup analyses by tumor histology were performed. RESULTS A total of 811 children were included (HB: 80.9%; HCC: 19.1%), of which 610 (75.2%) underwent surgical treatment. Following adjustment, decreased odds of undergoing surgical treatment were associated with Black race (OR: 0.46 vs White, 95% CI [95% CI]: 0.26-0.80, P = .01), and having Medicaid (OR: 0.58 vs private, 95% CI: 0.38-0.88, P = .01) or no insurance (OR: 0.33 vs private, 95% CI: 0.13-0.80, P = .02). In children with HB, Black race was associated with decreased odds of undergoing surgical treatment (OR: 0.47 vs White, 95% CI: 0.25-0.89, P = .02). In children with HCC, Medicaid (OR: 0.10 vs private, 95% CI: 0.03-0.35, P < .001), or no insurance status (OR: 0.10 vs private, 95% CI: 0.01-0.83, P = .03) were associated with decreased odds of undergoing surgical treatment. Other than metastatic disease, no additional factors were associated with likelihood of surgical treatment in any group. CONCLUSIONS Black race and having Medicaid or no insurance are independently associated with decreased odds of surgical treatment in children with HB and HCC, respectively. These children may be less likely to undergo curative surgery for their liver cancer.
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Affiliation(s)
- Ioannis A Ziogas
- Division of Pediatric Surgery, Children's Hospital Colorado, Aurora, CO; Department of Surgery, University of Colorado School of Medicine, Aurora, CO
| | - Jonathan P Roach
- Division of Pediatric Surgery, Children's Hospital Colorado, Aurora, CO; Department of Surgery, University of Colorado School of Medicine, Aurora, CO
| | - Shannon N Acker
- Division of Pediatric Surgery, Children's Hospital Colorado, Aurora, CO; Department of Surgery, University of Colorado School of Medicine, Aurora, CO
| | - Kristine S Corkum
- Division of Pediatric Surgery, Children's Hospital Colorado, Aurora, CO; Department of Surgery, University of Colorado School of Medicine, Aurora, CO
| | - Jose L Diaz-Miron
- Division of Pediatric Surgery, Children's Hospital Colorado, Aurora, CO; Department of Surgery, University of Colorado School of Medicine, Aurora, CO
| | - Ann M Kulungowski
- Division of Pediatric Surgery, Children's Hospital Colorado, Aurora, CO; Department of Surgery, University of Colorado School of Medicine, Aurora, CO
| | - Ankush Gosain
- Division of Pediatric Surgery, Children's Hospital Colorado, Aurora, CO; Department of Surgery, University of Colorado School of Medicine, Aurora, CO
| | - Jonathan L Hills-Dunlap
- Division of Pediatric Surgery, Children's Hospital Colorado, Aurora, CO; Department of Surgery, University of Colorado School of Medicine, Aurora, CO.
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11
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Abstract
Hepatoblastoma (HB) remains the most common paediatric liver tumour and survival in children with hepatoblastoma has improved considerably since the advent of sequential surgical regimens of chemotherapy based on platinum-based chemotherapeutic agents in the 1980s. With the advent of modern diagnostic imaging and pathology techniques, new preoperative chemotherapy regimens and the maturation of surgical techniques, new diagnostic and treatment options for patients with hepatoblastoma have emerged and international collaborations are investigating the latest diagnostic approaches, chemotherapy drug combinations and surgical strategies. Diagnosis of hepatoblastoma relies on imaging studies (such as ultrasound, computed tomography, and magnetic resonance imaging), alpha-fetoprotein (AFP) levels, and histological confirmation through biopsy. The standard treatment approach involves a multimodal strategy with neoadjuvant chemotherapy followed by surgical resection. In cases where complete resection is not feasible or tumors exhibit invasive characteristics, liver transplantation is considered. The management of metastatic and recurrent hepatoblastoma poses significant challenges, and ongoing research focuses on developing targeted therapies and exploring the potential of immunotherapy. Further studies are necessary to gain a better understanding of the etiology of hepatoblastoma, develop prevention strategies, and personalize treatment approaches. We aim to review the current status of diagnosis and treatment of hepatoblastoma.
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Affiliation(s)
- Yinbiao Cao
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, China
- The First Medical Center of the Chinese PLA General Hospital, Beijing, China
| | - Shurui Wu
- The First Medical Center of the Chinese PLA General Hospital, Beijing, China
| | - Haowen Tang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, China
- The First Medical Center of the Chinese PLA General Hospital, Beijing, China
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12
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O'Neill AF, Meyers RL, Katzenstein HM, Geller JI, Tiao GM, López-Terrada D, Malogolowkin M. Children's Oncology Group's 2023 blueprint for research: Liver tumors. Pediatr Blood Cancer 2023; 70 Suppl 6:e30576. [PMID: 37495540 PMCID: PMC10529117 DOI: 10.1002/pbc.30576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 07/06/2023] [Indexed: 07/28/2023]
Abstract
Liver tumors account for approximately 1%-2% of all pediatric malignancies, with the two most common tumors being hepatoblastoma (HB) and hepatocellular carcinoma (HCC). Previous Children's Oncology Group studies have meaningfully contributed to the current understanding of disease pathophysiology and treatment, laying groundwork for the ongoing prospective international study of both HB and HCC. Future work is focused on elucidating the biologic underpinnings of disease to support an evolution in risk categorization, advancements in the multidimensional care required to treat these patients, and the discovery of novel therapies.
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Affiliation(s)
- Allison F O'Neill
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
| | - Rebecka L Meyers
- Division of Pediatric Surgery, University of Utah, Salt Lake City, Utah, USA
| | | | - James I Geller
- Division of Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA
| | - Greg M Tiao
- Division of Surgery, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA
| | - Dolores López-Terrada
- Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, Texas, USA
| | - Marcio Malogolowkin
- Pediatric Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, California, USA
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13
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Somers KM, Tabbouche RB, Bondoc A, Towbin AJ, Ranganathan S, Tiao G, Geller JI. Retreatment with Cisplatin May Provide a Survival Advantage for Children with Relapsed/Refractory Hepatoblastoma: An Institutional Experience. Cancers (Basel) 2023; 15:3921. [PMID: 37568737 PMCID: PMC10416880 DOI: 10.3390/cancers15153921] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/15/2023] [Accepted: 06/23/2023] [Indexed: 08/13/2023] Open
Abstract
BACKGROUND Hepatoblastoma (HB) is the most common liver malignancy in children. There is no standard of care for management of relapsed/refractory HB (rrHB) and reports in the literature are limited. OBJECTIVE To describe presenting features, biology, treatment strategies, and outcomes for pediatric patients with relapsed/refractory hepatoblastoma. METHODS An IRB-approved retrospective institutional review of patients with rrHB who presented for consultation and/or care from 2000-2019. Clinical, radiographic, and histologic data were collected from all patients. RESULTS Thirty subjects were identified with a median age of 19.5 months (range 3-169 months) at initial diagnosis and 32.5 months (range 12-194 months) at time of first relapse. 63% of subjects were male, 70% Caucasian, and 13% were born premature. Three subjects had a known cancer predisposition syndrome. Eight patients had refractory disease while 22 patients had relapsed disease. Average time from initial diagnosis to relapse or progression was 12.5 months. Average alpha-fetoprotein (AFP) at initial diagnosis was 601,203 ng/mL (range 121-2,287,251 ng/mL). Average AFP at relapse was 12,261 ng/mL (range 2.8-201,000 ng/mL). For patients with tumor sequencing (n = 17), the most common mutations were in CTNNB1 (13) and NRF2 (4). First relapse sites were lungs (n = 12), liver (n = 11) and both (n = 6). More than one relapse/progression occurred in 47% of subjects; 6 had ≥3 relapses. Pathology in patients with multiply relapsed disease was less differentiated including descriptions of small cell undifferentiated (n = 3), pleomorphic (n = 1), transitional liver cell tumor (n = 2) and HB with carcinoma features (n = 1). All subjects underwent surgical resection of site of relapsed disease with 7 subjects requiring liver transplantation. Overall survival was 50%. Survival was associated with use of cisplatin at relapse (78.6% with vs. 25% without, p = 0.012). The most common late effect was ototoxicity with at least mild sensorineural hearing loss found in 80% of subjects; 54% required hearing aids. CONCLUSIONS Retreatment with cisplatin at the time of relapse may provide an advantage for some patients with hepatoblastoma. Multiply relapsed disease was not uncommon and not associated with a worse prognosis. Careful attention should be paid to cumulative therapy-induced toxicity while concurrently aiming to improve cure.
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Affiliation(s)
- Katherine M. Somers
- Division of Pediatric Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Rachel Bernstein Tabbouche
- Division of Pediatric Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Alexander Bondoc
- Department of Pediatric and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; (A.B.); (G.T.)
| | - Alexander J. Towbin
- Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA;
- Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Sarangarajan Ranganathan
- Department of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA;
| | - Greg Tiao
- Department of Pediatric and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; (A.B.); (G.T.)
| | - James I. Geller
- Division of Pediatric Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
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14
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Hamaya S, Oura K, Morishita A, Masaki T. Cisplatin in Liver Cancer Therapy. Int J Mol Sci 2023; 24:10858. [PMID: 37446035 DOI: 10.3390/ijms241310858] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/19/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver tumor and is often diagnosed at an unresectable advanced stage. Systemic chemotherapy as well as transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) are used to treat advanced HCC. TACE and HAIC have long been the standard of care for patients with unresectable HCC but are limited to the treatment of intrahepatic lesions. Systemic chemotherapy with doxorubicin or chemohormonal therapy with tamoxifen have also been considered, but neither has demonstrated survival benefits. In the treatment of unresectable advanced HCC, cisplatin is administered transhepatic arterially for local treatment. Subsequently, for cisplatin-refractory cases due to drug resistance, a shift to systemic therapy with a different mechanism of action is expected to produce new antitumor effects. Cisplatin is also used for the treatment of liver tumors other than HCC. This review summarizes the action and resistance mechanism of cisplatin and describes the treatment of the major hepatobiliary cancers for which cisplatin is used as an anticancer agent, with a focus on HCC.
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Affiliation(s)
- Sae Hamaya
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kita-gun 761-0793, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kita-gun 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kita-gun 761-0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kita-gun 761-0793, Japan
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15
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Bownes LV, Julson JR, Quinn CH, Hutchins SC, Erwin MH, Markert HR, Stewart JE, Mroczek-Musulman E, Aye J, Yoon KJ, Ohlmeyer M, Beierle EA. The Effects of Protein Phosphatase 2A Activation with Novel Tricyclic Sulfonamides on Hepatoblastoma. J Pediatr Surg 2023; 58:1145-1154. [PMID: 36907775 PMCID: PMC10198925 DOI: 10.1016/j.jpedsurg.2023.02.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 02/10/2023] [Indexed: 02/19/2023]
Abstract
BACKGROUND The tumor suppressor, protein phosphatase 2A (PP2A), is downregulated in hepatoblastoma. We aimed to examine the effects of two novel compounds of the tricyclic sulfonamide class, ATUX-3364 (3364) and ATUX-8385 (8385), designed to activate PP2A without causing immunosuppression, on human hepatoblastoma. METHODS An established human hepatoblastoma cell line, HuH6, and a human hepatoblastoma patient-derived xenograft, COA67, were treated with increasing doses of 3364 or 8385, and viability, proliferation, cell cycle and motility were investigated. Cancer cell stemness was evaluated by real-time PCR and tumorsphere forming ability. Effects on tumor growth were examined using a murine model. RESULTS Treatment with 3364 or 8385 significantly decreased viability, proliferation, cell cycle progression and motility in HuH6 and COA67 cells. Both compounds significantly decreased stemness as demonstrated by decreased abundance of OCT4, NANOG, and SOX2 mRNA. The ability of COA67 to form tumorspheres, another sign of cancer cell stemness, was significantly diminished by 3364 and 8385. Treatment with 3364 resulted in decreased tumor growth in vivo. CONCLUSION Novel PP2A activators, 3364 and 8385, decreased hepatoblastoma proliferation, viability, and cancer cell stemness in vitro. Animals treated with 3364 had decreased tumor growth. These data provide evidence for further investigation of PP2A activating compounds as hepatoblastoma therapeutics.
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Affiliation(s)
- Laura V Bownes
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Janet R Julson
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Colin H Quinn
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Sara Claire Hutchins
- Division of Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Michael H Erwin
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Hooper R Markert
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Jerry E Stewart
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | | | - Jamie Aye
- Division of Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Karina J Yoon
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | | | - Elizabeth A Beierle
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
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16
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Fahy AS, Brzezinski J, Ramphal R, Sayed BA. Surgical management of acutely ruptured hepatoblastoma with definitive oncologic resection. JOURNAL OF PEDIATRIC SURGERY CASE REPORTS 2023. [DOI: 10.1016/j.epsc.2023.102578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
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17
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Xie T, Hou D, Wang J, Zhao S. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as predictive markers in hepatoblastoma. Front Pediatr 2023; 11:904730. [PMID: 37124183 PMCID: PMC10130377 DOI: 10.3389/fped.2023.904730] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 03/24/2023] [Indexed: 05/02/2023] Open
Abstract
Background The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been presented to be a prognostic indicator in several cancers. We were supposed to evaluate the prognostic role of such inflammatory markers in hepatoblastoma (HB). Methods Total of 101 children, diagnosed with hepatoblastoma between January 2010 and January 2018, were enrolled before treatment in the study. The clinicopathological parameters, and outcomes were collected through laboratory analyses and patient follow-up. The association between NLR, PLR, and clinicopathological characters were analyzed with Wilcoxon test, Chi-Squared test, Kaplan-Meier, Log-rank and Cox regression analyses. Results NLR and PLR were significantly elevated in HB patients (P < 0.001), and related to age (P < 0.001), risk stratification system (P < 0.001), and pretreatment extent of disease (P < 0.0001). NLR was significantly related to alpha-fetoprotein (P = 0.034) and lactate dehydrogenase (P = 0.026). The 3-year overall survival (OS) and event-free survival (EFS) were poor in the high-NLR group (OS: 44.3% vs. 90.3%, P < 0.0001, EFS: 38.6% vs. 80.6%, P = 0.0001). The 3-year OS and EFS were poor in the high-PLR group (OS: 49.1% vs. 68.8%, P = 0.016, EFS: 39.6% vs. 64.6%, P = 0.0117). The multivariate analysis suggested that NLR (HR: 11.359, 95% CI: 1.218-105.947; P = 0.033) and risk stratification (HR: 44.905, 95% CI: 2.458-820.36; P = 0.01), were independent predictors of OS. Conclusion Our research showed that elevated NLR and PLR were the poor prognostic factors in HB patients before treatment. The NLR was an independent prognostic factor for OS.
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Affiliation(s)
- Tan Xie
- Pediatric Surgery Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dongliang Hou
- Pediatric Surgery, Henan Children's Hospital, Zhengzhou, China
| | - Jiaxiang Wang
- Pediatric Surgery Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Correspondence: Jiaxiang Wang Song Zhao
| | - Song Zhao
- Thoracic Surgery Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Correspondence: Jiaxiang Wang Song Zhao
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18
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Vasudevan SA, Meyers RL, Finegold MJ, López-Terrada D, Ranganathan S, Dunn SP, Langham MR, McGahren ED, Tiao GM, Weldon CB, Malogolowkin MH, Krailo MD, Piao J, Randazzo J, Towbin AJ, BethMcCarville M, O'Neill AF, Furman WL, Rodriguez-Galindo C, Katzenstein HM. Outcomes of children with well-differentiated fetal hepatoblastoma treated with surgery only: Report from Children's Oncology Group Trial, AHEP0731. J Pediatr Surg 2022; 57:251-256. [PMID: 35810020 PMCID: PMC9474653 DOI: 10.1016/j.jpedsurg.2022.05.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 05/13/2022] [Accepted: 05/24/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Hepatoblastoma (HB) requires surgical resection for cure, but only 20-30% of patients have resectable disease at diagnosis. Patients who undergo partial hepatectomy at diagnosis have historically received 4-6 cycles of adjuvant chemotherapy; however, those with 100% well-differentiated fetal histology (WDF) have been observed to have excellent outcomes when treated with surgery alone. PATIENTS AND METHODS Patients on the Children's Oncology Group non randomized, multicenter phase III study, AHEP0731, were stratified based on Evan's stage, tumor histology, and serum alpha-fetoprotein level at diagnosis. Patients were eligible for the very low risk stratum of surgery and observation if they had a complete resection at diagnosis and rapid central histologic review demonstrated HB with 100% WDF histology. RESULTS A total of 8 eligible patients were enrolled on study between September 14, 2009 and May 28, 2014. Outcome current to 06/30/2020 was used in this analysis. The median age at enrollment was 22.5 months (range: 8-84 months) and the median AFP at enrollment was 714 ng/ml (range: 18-77,747 ng/mL). With a median follow-up of 6.6 years (range: 3.6-9.8 years), the 5-year event-free (EFS) and overall survival (OS) were both 100%. CONCLUSION This report supports that HB with 100% WDF histology completely resected at diagnosis is curable with surgery only. The development of evidence-based surgical guidelines utilizing criteria based on PRETEXT group, vascular involvement (annotation factors), tumor-specific histology and corresponding biology will be crucial for optimizing which patients are candidates for resection at diagnosis followed by observation. LEVEL OF EVIDENCE Prognosis study, Level I evidence.
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Affiliation(s)
- Sanjeev A Vasudevan
- Baylor College of Medicine, Texas Children's Hospital, 6701 Fannin, Houston, TX 77030, United States
| | - Rebecka L Meyers
- Primary Children's Hospital, University of Utah, 100N. Mario Capecchi Dr., Salt Lake City, UT 84113, United States
| | - Milton J Finegold
- Baylor College of Medicine, Texas Children's Hospital, 6701 Fannin, Houston, TX 77030, United States
| | - Dolores López-Terrada
- Baylor College of Medicine, Texas Children's Hospital, 6701 Fannin, Houston, TX 77030, United States
| | - Sarangarajan Ranganathan
- Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, United States
| | - Stephen P Dunn
- AI Dupont Hospital for Children, 1600 Rockland Rd., Wilmington, DE 19803, United States
| | - Max R Langham
- St Jude Children's Research Hospital and University of Tennessee Health Science Center, 262 Danny Thomas Place, Memphis, TN 38015, United States
| | - Eugene D McGahren
- University of Virginia Hospital, 1215 Lee St., Charlottesville, VA 22903, United States
| | - Greg M Tiao
- Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, United States
| | - Christopher B Weldon
- Dana-Farber Cancer Institute and Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02115, United States
| | - Marcio H Malogolowkin
- University of California Davis Comprehensive Cancer Center, 2279 45th St., Sacramento, CA 95817, United States
| | - Mark D Krailo
- University of Southern California Keck School of Medicine, 1975 Zonal Ave., Los Angeles, CA 90033, United States
| | - Jin Piao
- University of Southern California Keck School of Medicine, 1975 Zonal Ave., Los Angeles, CA 90033, United States
| | - Jessica Randazzo
- Children's Oncology Group, 800 Royal Oaks Dr., Suite 210, Monrovia, CA 91016, United States
| | - Alexander J Towbin
- Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, United States
| | - M BethMcCarville
- St Jude Children's Research Hospital and University of Tennessee Health Science Center, 262 Danny Thomas Place, Memphis, TN 38015, United States
| | - Allison F O'Neill
- Dana-Farber Cancer Institute and Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02115, United States
| | - Wayne L Furman
- St Jude Children's Research Hospital and University of Tennessee Health Science Center, 262 Danny Thomas Place, Memphis, TN 38015, United States
| | - Carlos Rodriguez-Galindo
- St Jude Children's Research Hospital and University of Tennessee Health Science Center, 262 Danny Thomas Place, Memphis, TN 38015, United States
| | - Howard M Katzenstein
- Nemours Children's Hospital, 1600 Rockland Road, Wilmington DE 19803, United States.
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19
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Whitlock RS, Patel KR, Yang T, Nguyen HN, Masand P, Vasudevan SA. Pathologic correlation with near infrared-indocyanine green guided surgery for pediatric liver cancer. J Pediatr Surg 2022; 57:700-710. [PMID: 34049689 DOI: 10.1016/j.jpedsurg.2021.04.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 04/06/2021] [Accepted: 04/18/2021] [Indexed: 12/12/2022]
Abstract
PURPOSE Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the most common primary malignant tumors of childhood. Intraoperative indocyanine green (ICG) administration with near-infrared imaging (NIR) has emerged as a surgical technology that can be used to assist with localization of pulmonary metastases secondary to HB; however, there has been limited application as an adjunct for resection of the primary liver tumor and assessment of extrahepatic disease. METHODS We present 14 patients treated for HB, HCC, and malignant rhabdoid tumor at our institution with the use of intraoperative NIR-ICG guidance. All patients were treated with 0.2-0.75 mg/kg IV ICG, 48-96 h prior to surgery. Intraoperative NIR-ICG guided imaging was performed with several commercial devices. RESULTS Intraoperative NIR-ICG guidance allowed pulmonary metastasectomy in five patients using thoracoscopy or thoracotomy allowing for visualization of multiple nodules not seen on preoperative imaging most of which were positive for malignancy. NIR-ICG guidance allowed for assessment of extrahepatic extension in three patients; an HCC patient with extrahepatic lymph node extension of disease, an HB patient with extrapulmonary thoracic recurrence in the diaphragm and chest wall, and a patient with tumor rupture at diagnosis with peritoneal nodules at the time of surgery. This technique was used to guide partial hepatectomy in 11 patients for which the technique enabled successful identification of tumor and tumor margins. Three patients had nonspecific staining of the liver secondary to decreased timing from ICG injection to surgery or biliary obstruction. NIR-ICG enabled resection of satellite HB lesions in three multifocal patients and confirmed a benign satellite lesion in two additional patients. CONCLUSIONS Intraoperative use of NIR-ICG imaging during partial hepatectomy enabled enhanced identification and guidance for surgical resection of extrahepatic disease and multifocal liver tumors for the treatment of children with primary liver cancer.
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Affiliation(s)
- Richard S Whitlock
- Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX USA
| | - Kalyani R Patel
- Department of Pathology and Immunology, Texas Children's Hospital Liver Tumor Center, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX USA
| | - Tianyou Yang
- Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX USA
| | - HaiThuy N Nguyen
- Singleton Department of Pediatric Radiology, Texas Children's Hospital Liver Tumor Program, Baylor College of Medicine, Houston, TX USA
| | - Prakash Masand
- Singleton Department of Pediatric Radiology, Texas Children's Hospital Liver Tumor Program, Baylor College of Medicine, Houston, TX USA
| | - Sanjeev A Vasudevan
- Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX USA.
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20
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Watanabe K, Mori M, Hishiki T, Yokoi A, Ida K, Yano M, Fujimura J, Nogami Y, Iehara T, Hoshino K, Inoue T, Tanaka Y, Miyazaki O, Takimoto T, Yoshimura K, Hiyama E. Feasibility of dose-dense cisplatin-based chemotherapy in Japanese children with high-risk hepatoblastoma: Analysis of the JPLT3-H pilot study. Pediatr Blood Cancer 2022; 69:e29389. [PMID: 34606680 DOI: 10.1002/pbc.29389] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 08/29/2021] [Accepted: 09/14/2021] [Indexed: 11/09/2022]
Abstract
BACKGROUND The SIOPEL-4 study has demonstrated that dose-dense cisplatin-based chemotherapy dramatically improves outcome in children with high-risk hepatoblastoma in western countries. However, the feasibility and safety of this regimen have not been clarified in Japanese patients. METHODS A pilot study, JPLT3-H, was designed to evaluate the safety profile of the SIOPEL-4 regimen in Japanese children with newly diagnosed hepatoblastoma with either metastatic disease or low alpha-fetoprotein. RESULTS A total of 15 patients (three female) were enrolled. Median age was 2 years (range, 0-14). Three patients were PRETEXT II (where PRETEXT is PRETreatment EXTent of disease), six PRETEXT III, and six PRETEXT IV. All patients had lung metastasis, none had low alpha-fetoprotein. Eight patients completed the prescribed treatment, and seven patients discontinued therapy prematurely, four due to progressive disease and three due to causes other than severe toxicity. Grade 4 neutropenia was documented in most patients in preoperative cycles A1-3 (11/15 in A1, 9/11 in A2, and 7/11 in A3) and in all considering all cycles. Grade 3-4 thrombocytopenia and grade 3 anemia were also frequently observed. Patients experienced several episodes of grade 3 febrile neutropenia, but none had grade 4 febrile neutropenia or severe infections. One patient had grade 3 heart failure only in the first cycle. Other grade 3 or 4 toxicities were hypomagnesemia, anorexia, nausea, mucositis, liver enzyme elevation, fever, infection, and fatigue. There were no unexpected severe toxicities. CONCLUSION The toxicity profile of JPLT3-H was comparable to that of SIOPEL-4. Dose-dense cisplatin-based chemotherapy may be feasible among Japanese patients with high-risk hepatoblastoma.
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Affiliation(s)
- Kenichiro Watanabe
- Department of Hematology and Oncology, Shizuoka Children's Hospital, Shizuoka, Japan
| | - Makiko Mori
- Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan
| | - Tomoro Hishiki
- Department of Pediatric Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Akiko Yokoi
- Department of Pediatric Surgery, Kobe Children's Hospital, Kobe, Japan
| | - Kohmei Ida
- Department of Pediatrics, Teikyo University Mizonokuchi Hospital, Kawanagawa, Japan
| | - Michihiro Yano
- Department of Pediatrics, Akita University Hospital, Akita, Japan
| | - Junya Fujimura
- Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan
| | - Yuki Nogami
- Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Tomoko Iehara
- Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Ken Hoshino
- Department of Pediatric Surgery, Keio School of Medicine, Keio University, Tokyo, Japan
| | - Takeshi Inoue
- Department of Pathology, Osaka City General Hospital, Osaka, Japan
| | - Yukichi Tanaka
- Department of Pathology, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Osamu Miyazaki
- Department of Radiology, National Center for Child Health and Development, Tokyo, Japan
| | - Tetsuya Takimoto
- Department of Childhood Cancer Data Management, National Center for Child Health and Development, Tokyo, Japan
| | - Kenichi Yoshimura
- Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan
| | - Eiso Hiyama
- Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan.,Department of Pediatric Surgery, Hiroshima University Hospital, Hiroshima, Japan
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21
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Zhang YT, Zhao YF, Yang DF, Chang J. Retrospective Analysis of Pediatric Hepatoblastoma With Tumor Rupture: Experience From a Single Center. Front Pediatr 2022; 10:799307. [PMID: 35391745 PMCID: PMC8980550 DOI: 10.3389/fped.2022.799307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 02/08/2022] [Indexed: 11/13/2022] Open
Abstract
PURPOSE Hepatoblastoma (HB) tumor rupture is currently considered as a high-risk factor in some risk stratification systems. This study aimed to investigate the value of HB tumor rupture in predicting the poor prognosis. METHODS The clinical data from children with high-risk HB or HB tumor rupture at our institution from October 2008 to 2017 were retrospectively reviewed and analyzed. RESULTS Together, 34 children with high-risk HB or HB tumor rupture were retrospected, including 25 in the high-risk group and nine in tumor rupture group. The 3-year overall survival (OS) rate in tumor rupture group was significantly higher than that of the high-risk group (100 vs. 64%, p = 0.0427). In tumor rupture group, seven (77.8%) of nine patients had a hemoglobin level ≤ 8 g/L and 3 of them (33.3%) had ≤ 6 g/L at the time of diagnosis. Peritoneal perfusion with interleukin-2 was implemented for each patient. At the end of the treatment, seven (77.8%) of nine patients achieved complete response (CR). No patient died at the last follow-up. CONCLUSIONS HB tumor rupture might not be predictive of poor prognosis with the risk of peritoneal dissemination/relapse, in which peritoneal perfusion with interleukin-2 could play a role.
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Affiliation(s)
- Yu-Tong Zhang
- Department of Pediatric Oncology, The First Hospital of Jilin University, Changchun, China
| | - Yu-Fei Zhao
- Department of Pediatric Oncology, The First Hospital of Jilin University, Changchun, China
| | - Dian-Fei Yang
- Department of Pediatric Oncology, The First Hospital of Jilin University, Changchun, China
| | - Jian Chang
- Department of Pediatric Oncology, The First Hospital of Jilin University, Changchun, China
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22
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Illiano M, Colinard M, Taque S, Mallon B, Larue C, Laithier V, Vérité-Goulard C, Sudour-Bonnange H, Faure-Conter C, Coze C, Aerts I, De Maricourt CD, Paillard C, Branchereau S, Brugières L, Fresneau B. Long-term morbidity and mortality in 2-year hepatoblastoma survivors treated with SIOPEL risk-adapted strategies. Hepatol Int 2021; 16:125-134. [PMID: 34506008 DOI: 10.1007/s12072-021-10251-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 08/22/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND AND AIMS Prognosis of hepatoblastoma patients has increased with cisplatin-based chemotherapy and high-quality resection including liver transplant. Consequently current risk-adapted therapeutic strategy aims to reduce long-term side effects in patients with standard risk disease. METHODS We report long-term mortality and morbidity data concerning 151 2-year hepatoblastoma survivors treated with SIOPEL risk-adapted strategies (sex-ratio M/F = 1.6, median age at diagnosis = 2.6 years [range 0-17.7], median year at diagnosis = 2008 [1994-2017]). Fifty-three patients had loco-regional risk factors VPEFR, 12 were PRETEXT-IV and 30 were metastatic. All received cisplatin and 84 anthracyclines. Twelve had liver transplant. To assess hearing, renal and cardiac functions, audiograms were performed in 116/151 patients (76.8%), glomerular filtration rate in 113/151 (74.8%) and cardiac ultrasound in 65/84 (77.4%) anthracycline-exposed patients. RESULTS With a median follow-up of 9.4 years (range 2.1-25.8), four late relapses, one second malignancy (Acute Myeloid Leukemia AML-M5) and two deaths (one from hepatoblastoma, one from AML) occurred. The 10-years event free survival and overall survival probabilities were 95.5% (95% CI 91.9-99.1) and 98.7% (95% CI 96.8-100), respectively. Sixty-eight non-oncologic health-events included 57 cases of hearing loss (including 25 Brock 3-4), three liver cirrhosis, three pre-operative portal cavernoma, two focal nodular hyperplasia, two grade-1 chronic kidney diseases and one asymptomatic cardiac dysfunction were reported. Ototoxicity was significantly associated with cisplatin cumulative dose (OR = 2.07, 95% CI 1.32-3.24, p = 0.001) and carboplatin exposure (OR = 3.14, 95% CI 1.30-7.58, p = 0.01) in multivariable analysis adjusted for sex and age at diagnosis. CONCLUSIONS With current risk-adapted strategies, hepatoblastoma is a highly curable disease, with very rare relapses, and few late effects except hearing loss which remains a serious condition in these very young patients.
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Affiliation(s)
- M Illiano
- Department of Pediatric Oncology, Gustave Roussy, Université Paris-Saclay, 114 rue Edouard Vaillant, 94805, Villejuif, France
| | - M Colinard
- Department of Pediatric Oncology, CHU Reims, Reims, France
| | - S Taque
- Department of Pediatrics, CHU Rennes, Rennes, France
| | - B Mallon
- Department of Pediatric Oncology, Gustave Roussy, Université Paris-Saclay, 114 rue Edouard Vaillant, 94805, Villejuif, France
| | - C Larue
- Department of Pediatric Oncology, Gustave Roussy, Université Paris-Saclay, 114 rue Edouard Vaillant, 94805, Villejuif, France
| | - V Laithier
- Department of Pediatric Oncology, Hôpital Jean-Minjoz, Besançon, France
| | - C Vérité-Goulard
- Department of Pediatric Oncology, CHU de Bordeaux, Bordeaux, France
| | - H Sudour-Bonnange
- Department of Pediatrics and AYA Unit, Centre Oscar Lambret, Lille, France
| | - C Faure-Conter
- Institute of Pediatric Hematology and Oncology IHOPe, Lyon, France
| | - C Coze
- Department of Pediatric Onco-Hematology, Hôpital d'Enfants La Timone, Aix-Marseille University, APHM, Marseille, France
| | - I Aerts
- SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France
| | | | - C Paillard
- Department of Pediatric Oncology, Hôpital de Hautepierre, Strasbourg, France
| | - S Branchereau
- Department of Pediatric Surgery, CHU Kremlin Bicetre, Kremlin Bicetre, France
| | - L Brugières
- Department of Pediatric Oncology, Gustave Roussy, Université Paris-Saclay, 114 rue Edouard Vaillant, 94805, Villejuif, France
| | - B Fresneau
- Department of Pediatric Oncology, Gustave Roussy, Université Paris-Saclay, 114 rue Edouard Vaillant, 94805, Villejuif, France. .,Cancer and Radiation, CESP, Unit 1018 INSERM, Villejuif, France.
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23
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Imaging for Staging of Pediatric Abdominal Tumors: An Update, From the AJR Special Series on Cancer Staging. AJR Am J Roentgenol 2021; 217:786-799. [PMID: 33825502 DOI: 10.2214/ajr.20.25310] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The three most common pediatric solid tumors of the abdomen are neuroblastoma, Wilms tumor, and hepatoblastoma. These embryonal tumors most commonly present in the first decade of life. Each tumor has unique imaging findings, including locoregional presentation and patterns of distant spread. Neuroblastoma, Wilms tumor, and hepatoblastoma have unique staging systems that rely heavily on imaging and influence surgical and oncologic management. The staging systems include image-defined risk factors for neuroblastoma, the Children's Oncology Group staging system for Wilms tumor, and the pretreatment extent of tumor system (PRETEXT) for hepatoblastoma. It is important for radiologists to be aware of these staging systems to optimize image acquisition and interpretation. This article provides a practical and clinically oriented approach to the role of imaging in the staging of these common embryonal tumors of childhood. The selection among imaging modalities, key findings for determining tumor stage, and the role of imaging in posttreatment response evaluation and surveil-lance are discussed. Recent updates to the relevant staging systems are highlighted with attention to imaging findings of particular prognostic importance. The information presented will help radiologists tailor the imaging approach to the individual patient and guide optimal oncologic management.
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24
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Uchida H, Sakamoto S, Kasahara M, Ueno Y, Mochida S, Haga H, Okajima H, Eguchi S, Takada Y, Umeshita K, Kokudo N, Egawa H, Uemoto S, Ohdan H. An analysis of the outcomes in living donor liver transplantation for pediatric malignant hepatic tumors using nationwide survey data in Japan. Transpl Int 2021; 34:1408-1421. [PMID: 34021931 DOI: 10.1111/tri.13924] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 12/22/2022]
Abstract
Malignant hepatic tumors (MHTs) in children are rare and account for approximately 5% of candidates for pediatric liver transplantation (LT) in Japan. We conducted a national survey of pediatric patients undergoing living donor LT for MHTs between October 1990 and April 2018. In total, 116 children underwent LT for MHTs during this study period: 100 hepatoblastomas (HBLs), 10 hepatocellular carcinomas (HCCs), and six other MHTs. The overall patient survival rate at 5 years was 81.3% for HBL, 60.0% for HCC, and 80.0% for other MHTs (P = 0.047). In patients with HBL, there was no significant difference in the 1- and 5-year patient survival rates between patients undergoing primary LT and those who received salvage LT for tumor recurrence (89.7%, 81.6% vs. 88.0%, 76%; P = 0.526). The 5-year overall survival rate after LT for HBL significantly improved from 63.2% in 1996-2008 to 89.8% in 2009-2018 (P = 0.018). The presence of lung metastasis before LT had no significant influence on the long-term survival (P = 0.742). Five patients with HCC died, including two who fell outside the Milan criteria. In conclusion, LT for pediatric MHTs, especially HBL, is a valuable treatment option for select patients.
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Affiliation(s)
- Hajime Uchida
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Seisuke Sakamoto
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Mureo Kasahara
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan
| | - Satoshi Mochida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Hironori Haga
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Hideaki Okajima
- Department of Pediatric Surgery, Kanazawa Medical University, Ishikawa, Japan
| | - Susumu Eguchi
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Yasutsugu Takada
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Koji Umeshita
- Department of Surgery, Osaka University, Osaka, Japan
| | - Norihiro Kokudo
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
| | - Hiroto Egawa
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | | | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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25
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Lake CM, Bondoc AJ, Dasgupta R, Jenkins TM, Towbin AJ, Smith EA, Alonso MH, Geller JI, Tiao GM. Indocyanine green is a sensitive adjunct in the identification and surgical management of local and metastatic hepatoblastoma. Cancer Med 2021; 10:4322-4343. [PMID: 34117727 PMCID: PMC8267136 DOI: 10.1002/cam4.3982] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 04/17/2021] [Accepted: 04/26/2021] [Indexed: 11/25/2022] Open
Abstract
Background Hepatoblastoma is the most common primary pediatric liver malignancy. Indocyanine green (ICG) has been described as an adjunct to resection in small series. Its utility remains undefined in larger cohorts. Methods Records for 29 patients diagnosed with hepatoblastoma who received ICG prior to surgical resection from 2017 to 2020 at a single institution were retrospectively reviewed. The primary outcome was correlation between intraoperative ICG‐avidity and histologic presence of hepatoblastoma. A secondary outcome included the histologic margin designation for resected liver specimens. Results ICG sensitivity was 91% for 120 resected thoracic specimens from 21 patients. Specificity was 57%. In 10% of operations, HB‐positive specimens were resected solely on ICG‐avidity. In an additional 40% of cases, ICG assisted in localizing a preoperatively diagnosed lesion. ICG sensitivity during thoracotomy and thoracoscopic surgery was 95 and 74%, respectively; primary and relapsed disease demonstrated sensitivity of 94 and 73%, respectively. Sensitivity was 92% for 25 resected liver specimens from nine patients with all parenchymal margins grossly negative for disease. Four multifocal lesions were identified with two resected solely by ICG‐avidity. Conclusions ICG is a sensitive adjunct for identifying local and metastatic hepatoblastoma, including lesions not visualized on preoperative imaging, and delineating margins during liver resection. False positives limit specificity; however, there were no adverse outcomes from additional resections. We noted that thoracoscopic surgery can be completed safely in patients with less significant disease burden, and conversion to thoracotomy, if necessary, is straightforward.
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Affiliation(s)
- Charissa M Lake
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Alexander J Bondoc
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Roshni Dasgupta
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Todd M Jenkins
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Alexander J Towbin
- Department of Radiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Ethan A Smith
- Department of Radiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Maria H Alonso
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - James I Geller
- Division of Pediatric Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Gregory M Tiao
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
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26
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Outcome of staging chest CT and identification of factors associated with lung metastasis in children with hepatoblastoma. Eur Radiol 2021; 31:8850-8857. [PMID: 34031749 DOI: 10.1007/s00330-021-08047-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 04/06/2021] [Accepted: 05/05/2021] [Indexed: 10/21/2022]
Abstract
OBJECTIVES To evaluate the outcome of staging chest CT and to identify clinicoradiological factors predictive of lung metastasis in patients with hepatoblastoma based on the 2017 PRE-Treatment EXTent of tumor (PRETEXT) system. METHODS This bi-center study retrospectively identified patients diagnosed with hepatoblastoma between January 1998 and September 2019 in two tertiary hospitals. The primary outcome was the proportion of the patients who had lung metastasis at staging chest CT. The diagnostic accuracy of staging chest CT was calculated based on the 2017 PRETEXT criteria. The secondary outcome was the identification of factors predictive of lung metastasis using multivariable logistic regression. RESULTS In total, 123 patients (median age, 1 year; interquartile range, 0-4 years; 59 female) were included. Among those, 28% (35/123; 95% confidence interval [CI], 21-37%) had lung metastasis at staging chest CT. The overall accuracy of staging chest CT was 96.8%. The proportion of lung metastasis in patients with stage I, II, III, and IV was 0%, 24% (12 of 49; 95% CI, 14-38%), 23% (9 of 40; 95% CI, 12-38%), and 56% (14 of 25; 95% CI, 37-73%), respectively. Multifocality (adjusted odds ratio, 6.7; 95% CI, 2.7-17.5; p < .001) and male sex (adjusted odds ratio, 3.1; 95% CI, 1.2-8.6; p = .02) were associated with the presence of lung metastasis. CONCLUSIONS Twenty-eight percent of the patients with hepatoblastoma had lung metastasis at staging chest CT. Multifocality and male sex were predictive factors for lung metastasis on staging chest CT. KEY POINTS • The proportion of lung metastasis in patients with hepatoblastoma was 28%. • The overall accuracy of staging chest CT was 97% based on the 2017 PRETEXT system. • Hepatic tumor multifocality and male sex were predictors of lung metastasis.
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Koh KN, Namgoong JM, Yoon HM, Cho YA, Choi SH, Shin J, Kang SH, Suh JK, Kim H, Oh SH, Kim KM, Kim DY, Im HJ. Recent improvement in survival outcomes and reappraisal of prognostic factors in hepatoblastoma. Cancer Med 2021; 10:3261-3273. [PMID: 33939313 PMCID: PMC8124118 DOI: 10.1002/cam4.3897] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 02/09/2021] [Accepted: 03/18/2021] [Indexed: 02/06/2023] Open
Abstract
Background Prognostic factors in hepatoblastoma need to be reevaluated considering the advances in treatment modalities. The study aimed to evaluate current outcomes of hepatoblastoma and reappraise the association of prognostic factors, including pre‐treatment extent of tumor (PRETEXT) stage with annotation factors and Children's Hepatic tumors International Collaboration‐Hepatoblastoma Stratification (CHIC‐HS) system, with survival outcomes. Methods We evaluated 103 consecutive patients with hepatoblastoma retrospectively according to the treatment period based on the introduction of a liver transplantation program. Results The 5‐year overall survival (OS), event‐free survival (EFS), and transplant‐free survival rates were 80.2%, 74.2%, and 61.8%, respectively. EFS and OS were improved significantly from 58.6% to 81.6% (P = 0.024) and from 58.6% to 90.8% (P < 0.001), respectively, in the late period (N = 74) compared with the early period (N = 29). The PRETEXT stage was significant or marginally significant for EFS and OS in the early period but not in the late period. The P, F, R, and C factors were significant for OS and EFS in the early period. However, in the late period, only the P factor was significant for OS, and the F and M factors were significant for EFS. The CHIC‐HS system was significant or marginally significant for EFS in both the early and late periods; however, it was significant for OS only in the early period. Conclusion Survival rates were significantly improved in children with hepatoblastoma, especially in those with advanced PRETEXT stages with positive annotation factors and in a high‐risk CHIC‐HS group. Prognostic factors had different clinical implications with evolved treatment modalities.
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Affiliation(s)
- Kyung-Nam Koh
- Divison of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Jung-Man Namgoong
- Department of Pediatric Surgery, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Hee Mang Yoon
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young Ah Cho
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Se Hoon Choi
- Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Juhee Shin
- Divison of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung Han Kang
- Divison of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin Kyung Suh
- Divison of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyery Kim
- Divison of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Seak Hee Oh
- Divison of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung Mo Kim
- Divison of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Dae Yeon Kim
- Department of Pediatric Surgery, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Ho Joon Im
- Divison of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
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AlFawaz I, Ahmed B, Ali A, Ayas M, AlKofide A, Habib Z, Siddiqui K. Experience of treating pediatric hepatoblastoma at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia - Timely surgical intervention playing a key role. Int J Pediatr Adolesc Med 2021; 8:39-43. [PMID: 33718576 PMCID: PMC7922831 DOI: 10.1016/j.ijpam.2020.11.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 09/10/2020] [Accepted: 11/05/2020] [Indexed: 12/04/2022]
Abstract
BACKGROUND Many studies have demonstrated that outcome in patients with hepatoblastoma is determined by tumor resectability and the presence or absence of metastatic disease. PURPOSE To evaluate and disseminate information on diagnosis, treatment, and outcome of hepatoblastoma patients at a tertiary care hospital in Saudi Arabia. PATIENTS AND METHODS Twenty-four pediatric patients with hepatoblastoma were treated at our institution between January 2005 and December 2012. The majority of our patients were stage III and above, while one-third of them presented with metastatic disease. Four (16.7%) had vascular invasion. Two-thirds of our patients (n = 16, 66.7%) had alpha-fetoprotein (AFP) level above 100,000 ng/mL. Twenty-one patients underwent surgery; two had upfront surgery before getting any chemotherapy, and 15 had surgery on schedule after pre-operative chemotherapy. Four patients had delayed surgery as the tumor was not resectable and received extra cycles of chemotherapy. Chemotherapy regimens used were based on SIOPEL study protocols until 2011 and Children's Oncology Group (COG) protocol from 2012 onwards. Relapse, progressive disease, or death from any cause were defined as events. RESULTS Five-year overall survival (OS) of the cohort over a median follow-up time of 56.1 months was 70.6% ± 9.4% with seven (29.2%) events of mortality. No significant difference was found for age at diagnosis (less than 2 years vs. more), stage of disease, AFP levels (less than 100,000 vs. more), vascular invasion, or presence of metastatic disease at presentation in terms of OS. However, children receiving upfront or scheduled as-per-protocol surgery fared better than those who had delayed surgery (as the tumor was not resectable and they received extra cycles of chemotherapy) or did not undergo any surgery (P-Value .001). CONCLUSION Favorable survival outcome could be achieved with complete tumor excision and adjuvant chemotherapy. Inability to perform surgical excision was the single most important predictor of mortality in our patients.
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Affiliation(s)
- Ibrahim AlFawaz
- Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Basheer Ahmed
- Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Afshan Ali
- Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Mouhab Ayas
- Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Amani AlKofide
- Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Zakaria Habib
- Department of Surgery King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Khawar Siddiqui
- Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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Tian L, Chen T, Lu J, Yan J, Zhang Y, Qin P, Ding S, Zhou Y. Integrated Protein-Protein Interaction and Weighted Gene Co-expression Network Analysis Uncover Three Key Genes in Hepatoblastoma. Front Cell Dev Biol 2021; 9:631982. [PMID: 33718368 PMCID: PMC7953069 DOI: 10.3389/fcell.2021.631982] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 02/08/2021] [Indexed: 11/13/2022] Open
Abstract
Hepatoblastoma (HB) is the most common liver tumor in the pediatric population, with typically poor outcomes for advanced-stage or chemotherapy-refractory HB patients. The objective of this study was to identify genes involved in HB pathogenesis via microarray analysis and subsequent experimental validation. We identified 856 differentially expressed genes (DEGs) between HB and normal liver tissue based on two publicly available microarray datasets (GSE131329 and GSE75271) after data merging and batch effect correction. Protein–protein interaction (PPI) analysis and weighted gene co-expression network analysis (WGCNA) were conducted to explore HB-related critical modules and hub genes. Subsequently, Gene Ontology (GO) analysis was used to reveal critical biological functions in the initiation and progression of HB. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that genes involved in cell cycle phase transition and the PI3K/AKT signaling were associated with HB. The intersection of hub genes identified by both PPI and WGCNA analyses revealed five potential candidate genes. Based on receiver operating characteristic (ROC) curve analysis and reports in the literature, we selected CCNA2, CDK1, and CDC20 as key genes of interest to validate experimentally. CCNA2, CDK1, or CDC20 small interfering RNA (siRNA) knockdown inhibited aggressive biological properties of both HepG2 and HuH-6 cell lines in vitro. In conclusion, we identified CCNA2, CDK1, and CDC20 as new potential therapeutic biomarkers for HB, providing novel insights into important and viable targets in future HB treatment.
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Affiliation(s)
- Linlin Tian
- Department of Microbiology, Faculty of Basic Medical Sciences, Guilin Medical University, Guilin, China.,Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.,Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tong Chen
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.,Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of General Surgery, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jiaju Lu
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.,Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jianguo Yan
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, China
| | - Yuting Zhang
- Department of Microbiology, Faculty of Basic Medical Sciences, Guilin Medical University, Guilin, China
| | - Peifang Qin
- Department of Microbiology, Faculty of Basic Medical Sciences, Guilin Medical University, Guilin, China
| | - Sentai Ding
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.,Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yali Zhou
- Department of Microbiology, Faculty of Basic Medical Sciences, Guilin Medical University, Guilin, China.,Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, China
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Yin L, Chen L, Qi Z, Li J, Wang X, Ma K, Liu X. Gene expression-based immune infiltration analyses of liver cancer and their associations with survival outcomes. Cancer Genet 2021; 254-255:75-81. [PMID: 33647815 DOI: 10.1016/j.cancergen.2021.02.001] [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: 10/28/2020] [Revised: 01/21/2021] [Accepted: 02/02/2021] [Indexed: 12/09/2022]
Abstract
INTRODUCTION Liver cancer is one of the most lethal malignancies, presenting inferior survival outcomes once diagnosed. Current therapeutic approaches mainly target the tumor cells or vasculature, but rarely take the immune factors into consideration. METHODS In our study, the compositions of tumor-infiltrating immune cells (TIICs) in liver cancer and paracancer samples were analyzed based on the gene expression profiles by CIBERSORT. After calculating the proportions of 22 TIICs subtypes in 51 paired cancer and paracancer samples, we found their proportions varied between intragroup and intergroup. Compared with the paracancer tissues, the relative proportions of macrophages M0 and resting mast cells in liver cancer samples were significantly elevated, while that of M2 macrophages were reduced. RESULTS Univariate Cox regression analysis with the 22 TIICs subtypes as continuous variables showed increased B cells memory and resting NK cells were significantly associated with poor survival outcome. Besides, hierarchical clustering analysis based on the proportions of 22 TIICs subtypes identified 3 clusters, which exhibited distinct prognosis. Among them, cluster 1 had superior survival outcomes, while cluster 3 had inferior survival outcomes. CONCLUSIONS Collectively, our research suggested certain TIICs subpopulations proportions, as well as cluster patterns were associated with the prognosis of liver cancer, which provided potential therapeutic targets for liver cancer.
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Affiliation(s)
- Liang Yin
- Department of Pediatric Surgery, Cangzhou Central Hospital, Xinhua Road, Yunhe District, Cangzhou, Heibei 061000, China
| | - Lei Chen
- Department of Pediatric Surgery, Cangzhou Central Hospital, Xinhua Road, Yunhe District, Cangzhou, Heibei 061000, China
| | - Zilong Qi
- Department of Pediatric Surgery, Cangzhou Central Hospital, Xinhua Road, Yunhe District, Cangzhou, Heibei 061000, China
| | - Jinmin Li
- Department of Pediatric Surgery, Cangzhou Central Hospital, Xinhua Road, Yunhe District, Cangzhou, Heibei 061000, China
| | - Xinning Wang
- Department of Pediatric Surgery, Cangzhou Central Hospital, Xinhua Road, Yunhe District, Cangzhou, Heibei 061000, China
| | - Kun Ma
- Department of Pediatric Surgery, Cangzhou Central Hospital, Xinhua Road, Yunhe District, Cangzhou, Heibei 061000, China
| | - Xiangyang Liu
- Department of Pediatric Surgery, Cangzhou Central Hospital, Xinhua Road, Yunhe District, Cangzhou, Heibei 061000, China
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Ziogas IA, Benedetti DJ, Wu WK, Matsuoka LK, Izzy M, Rauf MA, Pai AK, Bailey CE, Alexopoulos SP. Management of hepatoblastoma in the United States: Can we do better? Surgery 2021; 170:579-586. [PMID: 33526266 DOI: 10.1016/j.surg.2020.12.035] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 12/22/2020] [Accepted: 12/26/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND Hepatoblastoma is the most common type of liver cancer in children. Refined therapeutic approaches combining risk-adapted chemotherapy along with complete tumor resection has led to improved survival. We aimed to evaluate the current state of management and outcomes for hepatoblastoma in the United States. METHODS We retrospectively reviewed 794 children (<18 years) with hepatoblastoma from the National Cancer Database (2004-2015). We assessed overall survival by means of Kaplan-Meier method, log-rank tests, and multivariable Cox regression. RESULTS Median age was 1 year (interquartile range: 0-2) and 170 (21.4%) presented with metastatic disease. Surgical resection was included in the treatment of 614 (77.3%) children (resection in 66.8% and liver transplantation in 10.6%). In the entire cohort, 95.1% of children received chemotherapy. In the surgical cohort, 575 (93.6%) received chemotherapy (34.5% neoadjuvant, 28.7% adjuvant, 30.5% both neoadjuvant and adjuvant). The 5-year overall survival was 76.6% for the entire cohort (no-surgery group: 55.3% vs surgery group: 82.8%). In multivariable analysis for all children, age ≥8 years (P = .009), metastasis (P < .001), surgery only (P = .009), and chemotherapy only (P < .001) were risk factors for mortality. In multivariable analysis for the surgical cohort, metastasis (P = .001), multifocality (P = .02), no chemotherapy (P = .03), and margin-positive resection (P = .02) were risk factors for mortality. CONCLUSION Excellent long-term overall survival is achievable with a combination of chemotherapy and surgical resection when a negative resection margin is achieved. However, nearly a quarter of children never received surgical treatment, representing a potential opportunity for improvement in care.
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Affiliation(s)
- Ioannis A Ziogas
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN. https://twitter.com/IA_Ziogas
| | - Daniel J Benedetti
- Department of Pediatrics, Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, TN
| | - W Kelly Wu
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN. https://twitter.com/WKellyWuMD
| | - Lea K Matsuoka
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN
| | - Manhal Izzy
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN. https://twitter.com/manhalizzy
| | - Muhammad A Rauf
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN
| | - Anita K Pai
- Department of Pediatrics, D. Brent Polk Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN
| | - Christina E Bailey
- Department of Surgery, Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN. https://twitter.com/TheRealDrBailey
| | - Sophoclis P Alexopoulos
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN.
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Weiss JBW, Wagner AE, Eberherr C, Häberle B, Vokuhl C, von Schweinitz D, Kappler R. High expression of IGF2-derived intronic miR-483 predicts outcome in hepatoblastoma. Cancer Biomark 2021; 28:321-328. [PMID: 32390604 DOI: 10.3233/cbm-191390] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND The role of microRNAs (miRs) as biomarkers to predict outcome in hepatoblastoma (HB), the most common malignant liver tumor in childhood, has still to be determined. Recently, the so-called four-miR signature has been described to efficiently stratify HB patients according to their prognosis. OBJECTIVE We examined the recently described four-miR signature for its clinical relevance in an independent validation cohort of HB patients and tried to optimize its predictive value by analyzing four additional miRs involved in HB biology. METHODS Expression of eight miR was determined in 29 tumor and 10 normal liver samples by TaqMan assays and association studies and Kaplan-Meier estimators determined their clinical relevance. RESULTS Stratifying HB patients by the four-miR signature showed no difference in patients' outcome, which was also reflected by the lack of association with any clinical risk parameter. Adding miR-23b-5p and miR-23b-3p did also not increase its discriminating power. However, the integration of miR-483-5p and miR-483-3p into the four-miR signature could predict patients with poor outcome that were associated with large tumors and vessel invasive growth with high accuracy. CONCLUSIONS The expansion of the four-miR signature by miR-483 serves as a useful biomarker to predict outcome of HB patients.
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Affiliation(s)
- Jakob Benjamin Wilhelm Weiss
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.,Department of Plastic and Hand Surgery, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Alexandra Elisabeth Wagner
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.,Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Corinna Eberherr
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Beate Häberle
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | | | - Dietrich von Schweinitz
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Roland Kappler
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
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Yu W, Liu X, Li J, Xi Z, Jin J, Huang H, Ge Y, Xia Q. A single-center retrospective analysis of childhood hepatoblastoma in China. Gland Surg 2020; 9:1502-1512. [PMID: 33224825 DOI: 10.21037/gs-20-710] [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: 11/06/2022]
Abstract
Background This study aimed to investigate the critical factors associated with prognosis for children with hepatoblastoma (HB) in mainland China combined with the aspect of health economics and management. Methods This study retrospectively reviewed children with HB in Renji Hospital Affiliated to the Shanghai Jiao Tong University School of Medicine from January 2013 to December 2019. Descriptive analysis was used to describe the essential characteristics. Kaplan-Meier method and Cox proportional hazard models were used to estimate the survival rate and prognosis factors. Results For the 87 children with HB, the average survival was 2,002.8 days (95% CI: 1,798.7-2,206.9 days), the 1- and 5-year survival rates were 87.7% and 78.9%, respectively. Undergoing surgery and sex were independent prognostic factors of childhood HB. Children with HB undergoing hepatectomy (HR: 0.039) or liver transplantation (HR: 0.142) had a better prognosis, while boys were associated with a poorer prognosis (HR: 3.614). The average medical expenses for childhood HB were 40,217.5±3,862.0 CNY and liver transplantation cost more than hepatectomy. Conclusions The results had a comparable survival rate with other studies globally. Surgical therapy and sex are associated with the prognosis of children with HB. The economic burden of childhood HB deserves to be further explored.
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Affiliation(s)
- Wenya Yu
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiang Liu
- Department of Respiratory Disease, The 903rd Hospital of PLA, Hangzhou, China
| | - Jingquan Li
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhifeng Xi
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Jin
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongting Huang
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yang Ge
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Moreno F, Rose A, Chaplin MA, Cipolla MC, García Lombardi M, Nana M, Cervio G, Halac E, Viso M, Ayarzabal V, Bosaleh A, Liberto D, Sarabia E, Rizzi A, Morici M, Streitenberger P, de Dávila MTG. Childhood liver tumors in Argentina: Incidence trend and survival by treatment center. A report from the national pediatric cancer registry, ROHA network 2000-2015. Pediatr Blood Cancer 2020; 67:e28583. [PMID: 32737960 DOI: 10.1002/pbc.28583] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 06/19/2020] [Accepted: 06/29/2020] [Indexed: 11/10/2022]
Abstract
BACKGROUND Information on the epidemiology of pediatric liver tumors in Latin America is limited. PURPOSE To describe the incidence of liver tumors in a pediatric registry in Argentina according to geographic region, national trends over 16 years, and survival related to stage, age, sex, and care center. METHODS Newly diagnosed liver tumors cases are registered in the Argentine Pediatric Oncology Hospital Registry (ROHA) with an estimated coverage of 91% of national cases. Age-standardized incidence rate per millon (ASR) was calculated based on the National Vital Statistics Reports. Five-year overall survival (OS) was estimated using the Kaplan-Meier method. The log-rank test was used to compare subgroup survival. RESULTS Two hundred seven cases of hepatoblastoma (HB) and 73 of hepatocellular carcinoma (HCC) were identified. ASR of liver tumors was 1.8/million (95% confidence Interval [CI], 1.6-2.0) per year. ASR was 1.4 (1.2-1.6) for HB and 0.4 (0.3-0.5) for HCC. For HB, the highest incidence was found in the northwest region including the Altiplano. OS was 60.4% (53.4-66.8) for HB and 36.1% (25.2-47.2) for HCC. Five-year survival rate of children with metastatic HB treated at liver transplant hospitals (LTH) was 54.2% (30.3-73.0) compared to 13.3% (2.2-34.6) for those seen at other hospitals (OH) (P = .02), while for HCC this rate was 46.3% (30.7-60.6) at LTH compared to 17.5% (3.1-41.9) at OH (P = .01). CONCLUSIONS The incidence rate of pediatric liver tumors was stable over the 16-year study period. Patients may benefit if at treatment initiation they are evaluated jointly with LTH specialists to define treatment strategies.
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Affiliation(s)
- Florencia Moreno
- Argentinian Pediatric Oncology Registry, Ministry of Health, National Cancer Institute, Buenos Aires, Argentina
| | - Adriana Rose
- Garrahan Pediatric Hospital, Buenos Aires, Argentina
| | - M Agustina Chaplin
- Argentinian Pediatric Oncology Registry, Ministry of Health, National Cancer Institute, Buenos Aires, Argentina
| | - M Cristina Cipolla
- Nacional Department of Maternity, Childhood, and Adolescence, Ministry of Health, Buenos Aires, Argentina
| | | | - Mariana Nana
- Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
| | | | - Esteban Halac
- Garrahan Pediatric Hospital, Buenos Aires, Argentina
| | | | | | | | | | - Elena Sarabia
- Dr Humberto J. Notti Children's Hospital, Mendoza, Argentina
| | - Ana Rizzi
- Garrahan Pediatric Hospital, Buenos Aires, Argentina
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Nagy M, Attya M, Patrinos GP. Unraveling heterogeneity of the clinical pharmacogenomic guidelines in oncology practice among major regulatory bodies. Pharmacogenomics 2020; 21:1247-1264. [PMID: 33124490 DOI: 10.2217/pgs-2020-0056] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Pharmacogenomics (PGx) implementation in clinical practice is steadily increasing. PGx uses genetic information to personalize medication use, which increases medication efficacy and decreases side effects. The availability of clinical PGx guidelines is essential for its implementation in clinical settings. Currently, there are few organizations/associations responsible for releasing those guidelines, including the Clinical Pharmacogenetics Implementation Consortium, Dutch Pharmacogenetics Working Group, the Canadian Pharmacogenomics Network for Drug Safety and the French National Network of Pharmacogenetics. According to the US FDA, oncology medications are highly correlated to PGx biomarkers. Therefore, summarizing the PGx guidelines for oncology drugs will positively impact the clinical decisions for cancer patients. This review aims to scrutinize side-by-side available clinical PGx guidelines in oncology.
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Affiliation(s)
- Mohamed Nagy
- Personalized Medication Management Unit, Children's Cancer Hospital Egypt (57357), Cairo, Egypt.,Department of Pharmaceutical Services, Children's Cancer Hospital Egypt (57357), Cairo, Egypt
| | - Mohamed Attya
- Department of Pharmaceutical Services, Children's Cancer Hospital Egypt (57357), Cairo, Egypt
| | - George P Patrinos
- Department of Pharmacy, University of Patras School of Health Sciences, Patras, Greece.,Zayed Center of Health Sciences, United Arab Emirates University, Al-Ain, UAE.,Department of Pathology, College of Medicine & Health Sciences, United Arab Emirates University, Al-Ain, UAE
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36
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Pondrom M, Pariente D, Mallon B, Taque S, Branchereau S, Chardot C, Laithier V, Tabone MD, Lejeune J, Faure-Conter C, Saumet L, Vérité C, Aerts I, Brugières L, Fresneau B. Tumor rupture in hepatoblastoma: A high risk factor? Pediatr Blood Cancer 2020; 67:e28549. [PMID: 32618436 DOI: 10.1002/pbc.28549] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 05/26/2020] [Accepted: 06/16/2020] [Indexed: 11/09/2022]
Abstract
BACKGROUND Hepatoblastoma tumor rupture is a high-risk criterion in the SIOPEL 3/4 protocol. Little is known about the outcome of these children. METHODS Radiological signs of possible tumor rupture, defined as peritoneal effusion, peritoneal nodules, or hepatic subcapsular hematoma, were reported in 24 of 150 patients treated for hepatoblastoma in France from January 2000 to December 2014 after central radiological expert review. RESULTS Twenty-two patients with available clinical data were included (nine PRETEXT-I/II, six PRETEXT-III, seven PRETEXT-IV, and five had lung metastases). Five patients had a subcapsular hematoma only, and 17 patients had intraperitoneal rupture (subcapsular hematoma and peritoneal effusion). A hepatic biopsy was performed in 19 patients. Intraperitoneal rupture occurred before biopsy in 12 and after biopsy in three (including one with prebiopsy subcapsular hematoma) (missing data: two). All patients were treated with chemotherapy, with high-risk regimens including cisplatin or carboplatin and doxorubicin in 19 and cisplatin or carboplatin alone in three. Liver surgery was performed in 20 patients (including three liver transplants). Fifteen patients (68%) achieved complete remission. With a median follow-up of 5.5 years, 11 events occurred (six progressions and three relapses, including three peritoneal progressions/relapses, one surgical complication, and one second cancer) and eight patients died. One of eight patients with no other high-risk criterion had a relapse. The three-year event-free survival and overall survival rates were 49.6% (95% CI = 30-69) and 68.2% (40-84), respectively. CONCLUSIONS Tumor rupture is predictive of poor prognosis with risk of peritoneal progression/relapse. However, it should not be a contraindication for liver transplantation.
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Affiliation(s)
- Morgane Pondrom
- Gustave Roussy, Department of Children and Adolescents Oncology, Université Paris-Saclay, Villejuif, France
| | - Daniele Pariente
- Centre hospitalier universitaire de Bicêtre, APHP, Department of Pediatric Radiology, Le Kremlin-Bicêtre, France
| | - Brenda Mallon
- Gustave Roussy, Department of Children and Adolescents Oncology, Université Paris-Saclay, Villejuif, France
| | - Sophie Taque
- Department of Pediatric Onco-hematology, Centre hospitalier universitaire, Rennes, France
| | - Sophie Branchereau
- Centre hospitalier universitaire de Bicêtre, APHP, Department of Pediatric Radiology, Le Kremlin-Bicêtre, France
| | - Christophe Chardot
- Department of Pediatric Surgery, Hôpital Necker-Enfants malades, Paris, France
| | - Véronique Laithier
- Department of Pediatric Onco-hematology, Centre hospitalier universitaire, Besançon, France
| | | | - Julien Lejeune
- Department of Pediatric Onco-hematology, Centre hospitalier universitaire, Tours, France
| | | | - Laure Saumet
- Department of Pediatric Onco-hematology, Centre hospitalier universitaire, Montpellier, France
| | - Cécile Vérité
- Department of Pediatric Onco-hematology, Centre hospitalier universitaire, Bordeaux, France
| | - Isabelle Aerts
- SIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), Paris, France
| | - Laurence Brugières
- Gustave Roussy, Department of Children and Adolescents Oncology, Université Paris-Saclay, Villejuif, France
| | - Brice Fresneau
- Gustave Roussy, Department of Children and Adolescents Oncology, Université Paris-Saclay, Villejuif, France.,Paris-Saclay University, CESP, INSERM, Paris-Sud University, Villejuif, France
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37
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Hsu WY, Chang HH, Lu MY, Yang YL, Jou ST, Chen HL, Ni YH, Hsu HY, Chang MH, Wu JF. Clinical risk stratification of children with SIOPEL high-risk hepatoblastoma in Taiwan. Pediatr Neonatol 2020; 61:393-398. [PMID: 32291200 DOI: 10.1016/j.pedneo.2020.03.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 08/16/2019] [Accepted: 03/18/2020] [Indexed: 10/24/2022] Open
Abstract
BACKGORUND Hepatoblastoma is the most common primary liver malignancy in young children. METHODS To identify predictors of the clinical outcomes of hepatoblastoma, we retrospectively reviewed the medical records of 45 children with hepatoblastoma in the National Taiwan University Hospital from 1998 to 2018. All of the children were classified as high risk according to the pretreatment extent of disease (PRETEXT) staging system. The patients' clinical data (sex, age at diagnosis, PRETEXT status, presence of metastasis or tumor rupture, tumor pathologic type, and clinical outcomes) were analyzed. RESULTS A total of 45 children with high-risk hepatoblastoma were diagnosed at an average age of 3.2 years. The survival analysis showed that the event-free survival duration was significantly longer in patients aged ≤1.25 years at diagnosis than those >1.25 years (hazard ratio = 2.86, p = 0.036). The absence of initial tumor rupture was associated with longer event-free survival (hazard ratio = 2.74, p = 0.039). Diagnosis at age >1.25 years was correlated with the presence of multifocal liver tumors (p = 0.0002) and tumor rupture at diagnosis (p = 0.02). There was no significant difference in event-free survival between the groups classified as intermediate versus high risk according to the Children's Hepatic tumors International Collaboration hepatoblastoma stratification system (p = 0.13). CONCLUSIONS Diagnosis at ≤ 1.25 years of age and absence of initial tumor rupture were predictive of a good clinical prognosis in Taiwanese children with hepatoblastoma.
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Affiliation(s)
- Wei-Yun Hsu
- Department of Pediatrics, Chi-Mei Medical Center, Tainan, Taiwan; Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Hsiu-Hao Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Meng-Yao Lu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Yung-Li Yang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Shiann-Tarng Jou
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
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38
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Haeberle B, Rangaswami A, Krailo M, Czauderna P, Hiyama E, Maibach R, Lopez-Terrada D, Aronson DC, Alaggio R, Ansari M, Malogolowkin MH, Perilongo G, O'Neill AF, Trobaugh-Lotrario AD, Watanabe K, Schmid I, von Schweinitz D, Ranganathan S, Yoshimura K, Hishiki T, Tanaka Y, Piao J, Feng Y, Rinaldi E, Saraceno D, Derosa M, Meyers RL. The importance of age as prognostic factor for the outcome of patients with hepatoblastoma: Analysis from the Children's Hepatic tumors International Collaboration (CHIC) database. Pediatr Blood Cancer 2020; 67:e28350. [PMID: 32383794 DOI: 10.1002/pbc.28350] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 03/24/2020] [Accepted: 03/30/2020] [Indexed: 12/27/2022]
Abstract
PURPOSE Treatment outcomes for hepatoblastoma have improved markedly in the contemporary treatment era, principally due to therapy intensification, with overall survival increasing from 35% in the 1970s to 90% at present. Unfortunately, these advancements are accompanied by an increased incidence of toxicities. A detailed analysis of age as a prognostic factor may support individualized risk-based therapy stratification. METHODS We evaluated 1605 patients with hepatoblastoma included in the CHIC database to assess the relationship between event-free survival (EFS) and age at diagnosis. Further analysis included the age distribution of additional risk factors and the interaction of age with other known prognostic factors. RESULTS Risk for an event increases progressively with increasing age at diagnosis. This pattern could not be attributed to the differential distribution of other known risk factors across age. Newborns and infants are not at increased risk of treatment failure. The interaction between age and other adverse risk factors demonstrates an attenuation of prognostic relevance with increasing age in the following categories: metastatic disease, AFP < 100 ng/mL, and tumor rupture. CONCLUSION Risk for an event increased with advancing age at diagnosis. Increased age attenuates the prognostic influence of metastatic disease, low AFP, and tumor rupture. Age could be used to modify recommended chemotherapy intensity.
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Affiliation(s)
- Beate Haeberle
- Division of Pediatric Surgery, University of Munich, Munich, Germany
| | - Arun Rangaswami
- Division of Pediatric Hematology and Oncology, University of California San Francisco, San Francisco, California
| | - Mark Krailo
- Department of Preventive Medicine, University of Southern California, California, Los Angeles
| | - Piotr Czauderna
- Department of Surgery for Children and Adolescents, Medical University of Gdansk, Gdansk, Poland
| | - Eiso Hiyama
- Department of Pediatric Surgery, Hiroshima University, Hiroshima, Japan
| | | | | | - Daniel C Aronson
- Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland
| | - Rita Alaggio
- Department of Pathology, Bambino Gesu Pediatric Hospital, Roma, Italy
| | - Marc Ansari
- Pediatric Department, Onco-Hematology Unit, Geneva University Hospital, Geneva, Switzerland
| | - Marcio H Malogolowkin
- Division of Pediatric Hematology Oncology, University of California Davis Comprehensive Cancer Center, California, Sacramento
| | | | - Allison F O'Neill
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Angela D Trobaugh-Lotrario
- Department of Pediatric Hematology/Oncology, Providence Sacred Heart Children's Hospital Spokane, Washington
| | - Kenichiro Watanabe
- Department of Hematology and Oncology, Shizuoka Children's Hospital, Shizuoka, Japan
| | - Irene Schmid
- Department of Pediatric Hematology and Oncology, University of Munich, Munich, Germany
| | | | - Sarangarajan Ranganathan
- Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Mediacla Center, Cincinnati, Ohio
| | - Kenichi Yoshimura
- Innovative Clinical Research Center (iCREK), Kanazawa University Hospital, Japan
| | - Tomoro Hishiki
- Department of Pediatric Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yukichi Tanaka
- Department of Pathology, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Jin Piao
- Department of Preventive Medicine, University of Southern California, California, Los Angeles
| | - Yurong Feng
- Children's Oncology Group, Los Angeles, California
| | | | | | | | - Rebecka L Meyers
- Division of Pediatric Surgery, University of Utah School of Medicine, Utah, Salt Lake City
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39
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Sekiguchi M, Seki M, Kawai T, Yoshida K, Yoshida M, Isobe T, Hoshino N, Shirai R, Tanaka M, Souzaki R, Watanabe K, Arakawa Y, Nannya Y, Suzuki H, Fujii Y, Kataoka K, Shiraishi Y, Chiba K, Tanaka H, Shimamura T, Sato Y, Sato-Otsubo A, Kimura S, Kubota Y, Hiwatari M, Koh K, Hayashi Y, Kanamori Y, Kasahara M, Kohashi K, Kato M, Yoshioka T, Matsumoto K, Oka A, Taguchi T, Sanada M, Tanaka Y, Miyano S, Hata K, Ogawa S, Takita J. Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets. NPJ Precis Oncol 2020; 4:20. [PMID: 32656360 PMCID: PMC7341754 DOI: 10.1038/s41698-020-0125-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 06/01/2020] [Indexed: 02/06/2023] Open
Abstract
Although hepatoblastoma is the most common pediatric liver cancer, its genetic heterogeneity and therapeutic targets are not well elucidated. Therefore, we conducted a multiomics analysis, including mutatome, DNA methylome, and transcriptome analyses, of 59 hepatoblastoma samples. Based on DNA methylation patterns, hepatoblastoma was classified into three clusters exhibiting remarkable correlation with clinical, histological, and genetic features. Cluster F was largely composed of cases with fetal histology and good outcomes, whereas clusters E1 and E2 corresponded primarily to embryonal/combined histology and poor outcomes. E1 and E2, albeit distinguishable by different patient age distributions, were genetically characterized by hypermethylation of the HNF4A/CEBPA-binding regions, fetal liver-like expression patterns, upregulation of the cell cycle pathway, and overexpression of NQO1 and ODC1. Inhibition of NQO1 and ODC1 in hepatoblastoma cells induced chemosensitization and growth suppression, respectively. Our results provide a comprehensive description of the molecular basis of hepatoblastoma and rational therapeutic strategies for high-risk cases.
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Affiliation(s)
- Masahiro Sekiguchi
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masafumi Seki
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tomoko Kawai
- Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Kenichi Yoshida
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Misa Yoshida
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tomoya Isobe
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Noriko Hoshino
- Department of Pediatric Surgery, The University of Tokyo Hospital, Tokyo, Japan
| | - Ryota Shirai
- Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - Mio Tanaka
- Department of Pathology, Kanagawa Children's Medical Center, Kanagawa, Japan
| | - Ryota Souzaki
- Department of Pediatric Surgery, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kentaro Watanabe
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yuki Arakawa
- Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan
| | - Yasuhito Nannya
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiromichi Suzuki
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoichi Fujii
- Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Keisuke Kataoka
- Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | - Yuichi Shiraishi
- Center for Cancer Genomics and Advanced Therapeutics, National Cancer Center Research Institute, Tokyo, Japan
| | - Kenichi Chiba
- Center for Cancer Genomics and Advanced Therapeutics, National Cancer Center Research Institute, Tokyo, Japan
| | - Hiroko Tanaka
- Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Teppei Shimamura
- Department of Systems Biology, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Yusuke Sato
- Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Aiko Sato-Otsubo
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shunsuke Kimura
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Pediatrics, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - Yasuo Kubota
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mitsuteru Hiwatari
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Katsuyoshi Koh
- Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan
| | | | - Yutaka Kanamori
- Division of Surgery, Department of Surgical Specialties, National Center for Child Health and Development, Tokyo, Japan
| | - Mureo Kasahara
- Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Kenichi Kohashi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Motohiro Kato
- Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - Takako Yoshioka
- Department of Pathology, National Center for Child Health and Development, Tokyo, Japan
| | - Kimikazu Matsumoto
- Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - Akira Oka
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tomoaki Taguchi
- Department of Pediatric Surgery, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masashi Sanada
- Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya, Japan
| | - Yukichi Tanaka
- Department of Pathology, Kanagawa Children's Medical Center, Kanagawa, Japan
| | - Satoru Miyano
- Center for Cancer Genomics and Advanced Therapeutics, National Cancer Center Research Institute, Tokyo, Japan
| | - Kenichiro Hata
- Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Seishi Ogawa
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto, Japan.,Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden
| | - Junko Takita
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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40
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Suh JK, Kang S, Kim H, Koh KN, Im HJ. Management of Hepatoblastoma in the Modern Era and Future Perspectives. CLINICAL PEDIATRIC HEMATOLOGY-ONCOLOGY 2020. [DOI: 10.15264/cpho.2020.27.1.43] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Affiliation(s)
- Jin Kyung Suh
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Sunghan Kang
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyery Kim
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung-Nam Koh
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Ho Joon Im
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
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41
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Sindhi R, Rohan V, Bukowinski A, Tadros S, de Ville de Goyet J, Rapkin L, Ranganathan S. Liver Transplantation for Pediatric Liver Cancer. Cancers (Basel) 2020; 12:cancers12030720. [PMID: 32204368 PMCID: PMC7140094 DOI: 10.3390/cancers12030720] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 03/10/2020] [Accepted: 03/12/2020] [Indexed: 02/06/2023] Open
Abstract
Unresectable hepatocellular carcinoma (HCC) was first removed successfully with total hepatectomy and liver transplantation (LT) in a child over five decades ago. Since then, children with unresectable liver cancer have benefitted greatly from LT and a confluence of several equally important endeavors. Regional and trans-continental collaborations have accelerated the development and standardization of chemotherapy regimens, which provide disease control to enable LT, and also serve as a test of unresectability. In the process, tumor histology, imaging protocols, and tumor staging have also matured to better assess response and LT candidacy. Significant trends include a steady increase in the incidence of and use of LT for hepatoblastoma, and a significant improvement in survival after LT for HCC with each decade. Although LT is curative for most unresectable primary liver sarcomas, such as embryonal sarcoma, the malignant rhabdoid tumor appears relapse-prone despite chemotherapy and LT. Pediatric liver tumors remain rare, and diagnostic uncertainty in some settings can potentially delay treatment or lead to the selection of less effective chemotherapy. We review the current knowledge relevant to diagnosis, LT candidacy, and post-transplant outcomes for these tumors, emphasizing recent observations made from large registries or larger series.
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Affiliation(s)
- Rakesh Sindhi
- Hillman Center for Pediatric Transplantation, UPMC-Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; (A.B.); (S.T.)
- Correspondence: ; Tel.: +1-412-692-7123
| | - Vinayak Rohan
- Medical University of South Carolina, Charleston, SC 29403, USA;
| | - Andrew Bukowinski
- Hillman Center for Pediatric Transplantation, UPMC-Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; (A.B.); (S.T.)
| | - Sameh Tadros
- Hillman Center for Pediatric Transplantation, UPMC-Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; (A.B.); (S.T.)
| | - Jean de Ville de Goyet
- Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), 90127 Palermo, Italy;
| | - Louis Rapkin
- Department of Hematology/Oncology, UPMC-Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA;
| | - Sarangarajan Ranganathan
- Department of Pathology, Children’s Hospital Medical Center of Cincinnati, Cincinnati, OH 45229, USA;
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42
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Tiusanen T, Hukkinen M, Leskinen O, Soini T, Kanerva JA, Jahnukainen T, Mäkisalo H, Heikinheimo M, Pakarinen MP. Incidence and long-term outcomes of surgically treated childhood hepatic malignancies in Finland. Acta Paediatr 2020; 109:404-414. [PMID: 31350767 DOI: 10.1111/apa.14952] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 06/06/2019] [Accepted: 07/24/2019] [Indexed: 12/12/2022]
Abstract
AIM To analyse incidence, treatment and outcomes of paediatric liver malignancies in Finland during 1987-2017. METHODS Medical records and national cancer registry data of 47 children with liver malignancies were reviewed. Survival was calculated with the Kaplan-Meier method. RESULTS During follow-up, liver malignancy incidence remained stable at 1.1:106 . Altogether, 42 patients with hepatoblastoma (n = 24), hepatocellular carcinoma (n = 11) and undifferentiated embryonal sarcoma (n = 7) underwent surgery at median age 4.6 (interquartile range, 2.0-9.6) years and were followed up for 13 (7.0-19) years. Cumulative 5-year survival was 86% for hepatoblastoma, 41% for hepatocellular carcinoma and 67% for undifferentiated embryonal sarcoma. Five-year survival was decreased among hepatoblastoma patients aged ≥ 2.4 years (73% versus 100%, P = .040), with PRETreatment EXTent of disease IV (PRETEXT, 60% vs 100%, P = .004), and with recurrent disease (67% vs 88%, P = .029). Recurrent/residual disease associated with decreased 5-year survival in hepatocellular carcinoma (0% vs 83%, P = .028). Survival was similar among 19 transplanted and 23 resected patients. In total, 14 deaths occurred either for the underlying malignancy (n = 8), adverse effects of chemotherapy (n = 5) or unrelated reasons (n = 1). CONCLUSION Outcomes for PRETEXT I-III hepatoblastoma and un-metastasized hepatocellular carcinoma were encouraging. Adverse effects of chemotherapy significantly contributed to mortality.
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Affiliation(s)
- Toivo Tiusanen
- Pediatric Liver and Gut Research Group Children's Hospital Helsinki University Hospital University of Helsinki Helsinki Finland
- Pediatric Research Center Children's Hospital Helsinki University Hospital University of Helsinki Helsinki Finland
| | - Maria Hukkinen
- Pediatric Liver and Gut Research Group Children's Hospital Helsinki University Hospital University of Helsinki Helsinki Finland
- Pediatric Research Center Children's Hospital Helsinki University Hospital University of Helsinki Helsinki Finland
- Section of Pediatric Surgery Children's Hospital Helsinki University Hospital University of Helsinki Helsinki Finland
| | - Outi Leskinen
- HUS Medical Imaging Center Children's Hospital Helsinki University Hospital University of Helsinki Helsinki Finland
| | - Tea Soini
- Pediatric Research Center Children's Hospital Helsinki University Hospital University of Helsinki Helsinki Finland
| | - Jukka A. Kanerva
- Pediatric Research Center Children's Hospital Helsinki University Hospital University of Helsinki Helsinki Finland
| | - Timo Jahnukainen
- Pediatric Research Center Children's Hospital Helsinki University Hospital University of Helsinki Helsinki Finland
- Department of Pediatric Nephrology and Transplantation Children's Hospital Helsinki University Hospital University of Helsinki Helsinki Finland
| | - Heikki Mäkisalo
- Department of Liver and Transplantation Surgery University Hospital University of Helsinki Helsinki Finland
| | - Markku Heikinheimo
- Pediatric Research Center Children's Hospital Helsinki University Hospital University of Helsinki Helsinki Finland
- Department of Pediatrics Washington University St. Louis MO USA
| | - Mikko P. Pakarinen
- Pediatric Liver and Gut Research Group Children's Hospital Helsinki University Hospital University of Helsinki Helsinki Finland
- Pediatric Research Center Children's Hospital Helsinki University Hospital University of Helsinki Helsinki Finland
- Section of Pediatric Surgery Children's Hospital Helsinki University Hospital University of Helsinki Helsinki Finland
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43
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Angelico R, Grimaldi C, Gazia C, Saffioti MC, Manzia TM, Castellano A, Spada M. How Do Synchronous Lung Metastases Influence the Surgical Management of Children with Hepatoblastoma? An Update and Systematic Review of the Literature. Cancers (Basel) 2019; 11:1693. [PMID: 31683629 PMCID: PMC6895839 DOI: 10.3390/cancers11111693] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 10/23/2019] [Accepted: 10/29/2019] [Indexed: 12/11/2022] Open
Abstract
Approximately 20% of children with hepatoblastoma (HB) have metastatic disease at diagnosis, most frequently in the lungs. In children with HB, lung metastatic disease is associated with poorer prognosis. Its treatment has been approached with a variety of methods that integrate chemotherapy and surgical resection. The timing and feasibility of complete extirpation of lung metastases, by chemotherapy and/or metastasectomy, is crucial for the surgical treatment of the primary liver tumor, which can vary from major hepatic resections to liver transplantation (LT). In children with unresectable HB, which can be surgically treated only by LT, the persistence of unresectable metastases after neoadjuvant chemotherapy excludes the possibility of recurring to LT with consequent negative impact on patients' outcomes. Due to limited evidence and experience, there is no consensus amongst oncologists and surgeons across institutions regarding the surgical treatment for HB with synchronous metastatic lung disease. This narrative review aimed to update the current management of pulmonary metastasis in children with HB and to define its role in the decision-making strategy for the surgical approach to primary liver tumours.
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Affiliation(s)
- Roberta Angelico
- Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children's Hospital IRCCS, 00165 Rome, Italy.
| | - Chiara Grimaldi
- Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children's Hospital IRCCS, 00165 Rome, Italy.
| | - Carlo Gazia
- Department of Surgery Science, HPB and Transplantation Unit, University of Rome Tor Vergata, 00133 Rome, Italy.
| | - Maria Cristina Saffioti
- Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children's Hospital IRCCS, 00165 Rome, Italy.
| | - Tommaso Maria Manzia
- Department of Surgery Science, HPB and Transplantation Unit, University of Rome Tor Vergata, 00133 Rome, Italy.
| | - Aurora Castellano
- Division of Oncohematology, Bambino Gesù Children's Hospital IRCCS, 00165 Rome, Italy.
| | - Marco Spada
- Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children's Hospital IRCCS, 00165 Rome, Italy.
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Yoon HM, Hwang J, Kim KW, Namgoong JM, Kim DY, Koh KN, Kim H, Cho YA. Prognostic Factors for Event-Free Survival in Pediatric Patients with Hepatoblastoma Based on the 2017 PRETEXT and CHIC-HS Systems. Cancers (Basel) 2019; 11:cancers11091387. [PMID: 31540387 PMCID: PMC6769992 DOI: 10.3390/cancers11091387] [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] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 09/11/2019] [Accepted: 09/11/2019] [Indexed: 11/16/2022] Open
Abstract
This study aimed to evaluate the prognostic value of variables used in the 2017 PRE-Treatment EXTent of tumor (PRETEXT) system and the Children's Hepatic tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) system in pediatric patients with hepatoblastoma. A retrospective analysis of data from the pediatric hepatoblastoma registry of a tertiary referral center was conducted to evaluate the clinical and imaging variables (annotation factors) of the PRETEXT staging system. The primary outcome was event-free survival (EFS). Data from 84 patients (mean age: 2.9 ± 3.5 years) identified between 1998 and 2017 were included. Univariable Cox proportional hazards analysis revealed that PRETEXT annotation factors P (portal vein involvement), F (multifocality of tumor), and M (distant metastasis) showed a significant negative association with EFS. Multivariable Cox proportional hazard analysis showed that factor F was the strongest predictor (HR (hazard ratio), 2.908; 95% CI (confidence interval), 1.061-7.972; p = 0.038), whereas factor M showed borderline significance (HR, 2.416; 95% CI, 0.918-6.354; p = 0.074). The prediction model based on F and M (F + M) showed good performance to predict EFS (C-statistic, 0.734; 95% CI, 0.612-0.854). In conclusion, the PRETEXT annotation factor F was the strongest predictor of EFS, and the F + M model showed good performance to predict EFS in pediatric patients with hepatoblastoma.
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Affiliation(s)
- Hee Mang Yoon
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
| | - Jisun Hwang
- Department of Radiology, Dongtan Sacred Heart Hospital, Hallym University Medical Center, Hwaseong 18450, Korea.
| | - Kyung Won Kim
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
| | - Jung-Man Namgoong
- Department of Pediatric Surgery, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 05505, Korea.
| | - Dae Yeon Kim
- Department of Pediatric Surgery, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 05505, Korea.
| | - Kyung-Nam Koh
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 05505, Korea.
| | - Hyery Kim
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 05505, Korea.
| | - Young Ah Cho
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
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Retrospective Analysis of Childhood Hepatoblastoma in a Single Centre in China. Clin Oncol (R Coll Radiol) 2019; 31:471-478. [PMID: 31000431 DOI: 10.1016/j.clon.2019.03.044] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 02/27/2019] [Accepted: 02/28/2019] [Indexed: 01/23/2023]
Abstract
AIMS To investigate the protocol efficacy and prognostic factors for paediatric hepatoblastoma in a multidisciplinary model in our centre. MATERIALS AND METHODS Consecutive hepatoblastoma patients (<18 years old) treated at Shanghai Children's Medical Center in China from August 2011 to October 2017 were analysed retrospectively for clinical features, chemotherapy courses, surgical treatment and outcomes. RESULTS One hundred and four cases of paediatric hepatoblastoma (64 males, 40 females; median age at diagnosis 1.64 years) had a median follow-up of 30.68 months (range 8.3-73.3 months). First complete remission was achieved in 95 cases, 85 of which achieved continuous complete remission. Another three cases were lost to follow-up after a median of 24.73 months in complete remission. Seven cases relapsed later, with two achieving a second complete remission and four deaths. Nine cases did not achieve complete remission and five of them died. In general, the 5-year overall survival rate and 5-year event-free survival (EFS) rate were 86.3 ± 5.0% and 81.8 ± 4.3%, respectively. Thirty-two cases were classified as standard risk and 72 as high risk with 5-year EFS of 96.8 ± 3.2% and 75.7 ± 5.7% (P = 0.029) and 5-year overall survival of 100% and 80.5 ± 7.0%, respectively. The mean platelet count (P = 0.0036), lactate dehydrogenase (P = 0.0443) and ferritin level (P = 0.0006) at diagnosis were much higher in the high-risk group than in the standard-risk group. Univariate analysis showed that patients <5 years of age (P = 0.018), with higher α-fetoprotein (AFP) level (>100 ng/ml, P = 0.008), without metastases at diagnosis (P = 0.001) and postoperative AFP recovery after no more than three chemocycles (P = 0.014) had better overall survival. In addition, the above factors, except metastases at diagnosis and risk group, were associated with prognosis in the multivariate analysis. CONCLUSIONS The result of this protocol had similar overall survival and EFS rates compared with those in developed countries. Normal postoperative AFP levels after three chemocycles has prognostic value.
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Minimal adjuvant chemotherapy for children with hepatoblastoma resected at diagnosis (AHEP0731): a Children's Oncology Group, multicentre, phase 3 trial. Lancet Oncol 2019; 20:719-727. [PMID: 30975630 DOI: 10.1016/s1470-2045(18)30895-7] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 11/15/2018] [Accepted: 11/16/2018] [Indexed: 11/23/2022]
Abstract
BACKGROUND Hepatoblastoma treatment with curative intent requires surgical resection, but only about a third of newly diagnosed patients with hepatoblastoma have resectable disease at diagnosis. Patients who have upfront resection typically receive a total of 4-6 cycles of adjuvant chemotherapy post-surgery, with the combination of cisplatin, fluorouracil, and vincristine. We aimed to investigate whether event-free survival in children with hepatoblastoma who had complete resection at diagnosis could be maintained with two cycles of adjuvant chemotherapy. METHODS In this Children's Oncology Group, multicentre, phase 3 trial, patients were enrolled in four risk groups on the basis of Evans surgical stage, tumour histology, and levels of α-fetoprotein at diagnosis to receive risk-adapted therapy. Here, we report on the low-risk stratum of the trial. Eligible patients were younger than 21 years and had histologically confirmed, stage I or II hepatoblastoma without 100% pure fetal stage I or small-cell undifferentiated histology; elevated serum α-fetoprotein level (>100 ng/mL); a complete resection at diagnosis; at least 50% Karnofsky (patients >16 years) or Lansky (patients ≤16 years) performance status; and had received no previous chemotherapy or other hepatoblastoma-directed therapy. Patients received two 21-day cycles of cisplatin, fluorouracil, and vincristine within 42 days of resection, consisting of cisplatin (100 mg/m2 per dose or 3·3 mg/kg per dose for children <10 kg) intravenously over 6 h on day 1; fluorouracil (600 mg/m2 per dose or 20 mg/kg per dose for children <10 kg) intravenous push on day 2; and vincristine (1·5 mg/m2 per day to a maximum dose of 2 mg, or 0·05 mg/kg per day for children <10 kg) intravenous push on days 2, 9, and 16. The primary outcome was investigator-assessed event-free survival. As prespecified by protocol, we analysed the primary endpoint 6 years after enrolment (cutoff date June 30, 2017). This trial is registered with ClinicalTrials.gov, number NCT00980460, and is now permanently closed to accrual. FINDINGS Between May 18, 2010, and May 28, 2014, 51 patients in 32 centres in two countries were enrolled into the low-risk stratum of this trial, of whom 49 received c hemotherapy treatment after surgery and were evaluable for activity and safety. Median follow-up time for all evaluable patients was 42 months (IQR 36-62). 4-year event-free survival was 92% (95% CI 79-97) and 5-year event-free survival was 88% (72-95). Two (4%) of 49 patients had surgical complications (bile leaks). The most common grade 3-4 adverse events were febrile neutropenia in seven (14%) patients, decreased neutrophil count in three (6%) patients, infections in four (8%) patients, and diarrhoea in four (8%) patients. Ototoxicity occurred in one (2%) patient. One (2%) patient of the three who relapsed in this cohort died from disease. Two (4%) patients died in clinical remission after therapy discontinuation. One patient died of pneumonia and bacterial sepsis 1 year after therapy discontinuation and another patient died of unrelated causes 57 months after therapy completion. There were no treatment-related deaths. INTERPRETATION Minimal postoperative chemotherapy with two cycles of cisplatin, fluorouracil, and vincristine can ensure disease control in patients with hepatoblastoma resected at diagnosis. Our results show that dose reduction of ototoxic agents is a safe, effective treatment for these children. FUNDING National Institutes of Health.
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47
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Disease-specific Hospitalizations Among 5-Year Survivors of Hepatoblastoma: A Nordic Population-based Cohort Study. J Pediatr Hematol Oncol 2019; 41:181-186. [PMID: 30557167 DOI: 10.1097/mph.0000000000001378] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
INTRODUCTION The long-term risk of somatic disease in hepatoblastoma survivors has not been thoroughly evaluated in previous studies. In this population-based study of 86 five-year HB survivors, we used inpatient registers to evaluate the risk for a range of somatic diseases. METHODS In total, 86 five-year survivors of hepatoblastoma were identified in the Nordic cancer registries from 1964 to 2008 and 152,231 population comparisons were selected. Study subjects were followed in national hospital registries for somatic disease classified into 12 main diagnostic groups. Standardized hospitalization rate ratios (RRs) and absolute excess risks were calculated. RESULTS After a median follow-up of 11 years, 35 of the 86 five-year hepatoblastoma survivors had been hospitalized with a total of 69 hospitalizations, resulting in an RR of 2.7 (95% confidence interval [CI], 2.2-3.5) and an overall absolute excess risk of 4.2 per 100 person-years. Highest risk was seen for benign neoplasms (RR=16) with 6 hospitalizations for benign neoplasms in the colon and one in rectum. CONCLUSIONS The pattern of hospitalizations found in this first comprehensive follow-up of hepatoblastoma survivors seems reassuring. Less than 50% of the 5-year survivors had been hospitalized and often for diseases that were not severe or life-threatening.
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48
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Aronson DC, Weeda VB, Maibach R, Czauderna P, Dall’Igna P, de Ville de Goyet J, Branchereau S, Perilongo G, Brock P, Zsiros J, Semeraro M, Chardot C, Wildhaber B, Morland B, Brugières L. Microscopically positive resection margin after hepatoblastoma resection: what is the impact on prognosis? A Childhood Liver Tumours Strategy Group (SIOPEL) report. Eur J Cancer 2019; 106:126-132. [DOI: 10.1016/j.ejca.2018.10.013] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 10/08/2018] [Accepted: 10/22/2018] [Indexed: 12/21/2022]
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49
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Ren X, Li H, Diao M, Chen L, Xu H, Li L. Results of surgical resections with positive margins for children with hepatoblastoma: Case series from a single Asian center. Pediatr Blood Cancer 2019; 66:e27479. [PMID: 30255649 DOI: 10.1002/pbc.27479] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 08/25/2018] [Accepted: 09/10/2018] [Indexed: 01/16/2023]
Abstract
The influence of margin status on the survival of patients with hepatoblastoma (HB) remains controversial. Here, we report long-term follow-up outcomes of 26 patients with HB who underwent hepatectomy with positive microscopic margins. Although these patients had microscopic residuals, the 5-year overall survival and event-free survival rates of those who had no metastases or macrovascular involvement (MVI) were 86.7% and 80.8%, respectively. This may support the hypothesis that patients with HB who undergo hepatectomy with positive microscopic residuals but without MVI or metastases can also achieve satisfactory survival rate. Further studies in this field are required.
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Affiliation(s)
- Xianghai Ren
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, People's Republic of China.,Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Haibo Li
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, People's Republic of China.,Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Mei Diao
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, People's Republic of China
| | - Long Chen
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, People's Republic of China.,Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Hang Xu
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, People's Republic of China.,Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Long Li
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, People's Republic of China
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50
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von Frowein J, Hauck SM, Kappler R, Pagel P, Fleischmann KK, Magg T, Cairo S, Roscher A, von Schweinitz D, Schmid I. MiR-492 regulates metastatic properties of hepatoblastoma via CD44. Liver Int 2018; 38:1280-1291. [PMID: 29314711 DOI: 10.1111/liv.13687] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 12/18/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS MicroRNAs are important genetic regulators of physiological and pathophysiological processes including cancer initiation and progression of hepatoblastoma, the most common liver tumour in childhood. We aimed to identify malignant and metastasis promoting effects of miR-492, a miRNA, previously reported to be overexpressed in metastatic hepatoblastoma. Furthermore, we intended to evaluate its diagnostic and prognostic potential. METHODS Stable and transient overexpression of miR-492 in two liver tumour cell lines HepT1 and HUH7 was used to analyse features of metastatic tumour progression such as proliferation, anchorage-independent growth, migration and invasion. Via a mass spectrometry based proteomic screen, we investigated miRNA-492-dependent effects on proteome level and explored the underlying biology. One of the predicted target genes, CD44, was experimentally validated via luciferase assays. Diagnostic and prognostic properties of miR-492 were studied in hepatoblastoma tumour samples. RESULTS We show that miR-492 significantly enhances cell proliferation, anchorage-independent growth, migration and invasion of hepatoblastoma cells. We also identified and validated CD44, a transmembrane adhesion receptor for hyaluronan, as direct and functional target of miR-492. This miRNA has a strong direct impact on two CD44 isoforms (standard and v10). High miR-492 expression correlates with high-risk or aggressive tumours and further bears potential for predicting reduced event-free survival. CONCLUSIONS We identified miR-492 and its target CD44 as regulators of a number of biological features important for malignancy and metastasis. Furthermore, we demonstrated the diagnostic and prognostic potential of miR-492, a promising novel therapeutic target and biomarker for hepatoblastoma.
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Affiliation(s)
- Julia von Frowein
- Department of Pediatric Hematology and Oncology, Children's Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Stefanie M Hauck
- Research Unit Protein Science, Helmholtz Zentrum Munich (GmbH), German Research Center for Environmental Health, Munich, Germany
| | - Roland Kappler
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Philipp Pagel
- Lehrstuhl für Genomorientierte Bioinformatik, Technische Universität München, Freising, Germany.,numares AG, Regensburg, Germany
| | - Katrin K Fleischmann
- Department of Pediatric Hematology and Oncology, Children's Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Thomas Magg
- Department of Pediatric Hematology and Oncology, Children's Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Stefano Cairo
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.,XenTech, Evry, France
| | - Adelbert Roscher
- Children's Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Dietrich von Schweinitz
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Irene Schmid
- Department of Pediatric Hematology and Oncology, Children's Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
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