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Ozer G, Ozcan HN, Ardicli B, Kutluk T, Oguz B, Haliloglu M. Radiological and clinical signatures to differentiate hepatocellular carcinoma from hepatoblastoma in children older than 5 years of age: a feasibility study. Pediatr Radiol 2025; 55:946-954. [PMID: 39961817 PMCID: PMC12065736 DOI: 10.1007/s00247-025-06190-w] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 01/30/2025] [Accepted: 02/03/2025] [Indexed: 04/12/2025]
Abstract
BACKGROUND Hepatoblastoma and hepatocellular carcinoma (HCC) are the most common primary malignant liver tumors in children. Although some characteristic imaging findings have been described in both hepatoblastoma and HCC, it is difficult to distinguish between these two tumors over the 5 years of age. OBJECTIVE To investigate clinical and radiological findings that may help differentiate hepatoblastoma and HCC over 5 years of age. MATERIALS AND METHODS From 2007 to 2022, 19 consecutive patients older than 5 years old diagnosed with primary liver malignancy were yielded from our radiology archive retrospectively. Imaging features, age, sex, treatment, and follow-up data were recorded. RESULTS A total of 19 patients (16 boys; median age 7.5, min-max 5-17), ten HCCs and nine hepatoblastomas, were included. Serum alpha-fetoprotein (sAFP) values were significantly higher in hepatoblastoma patients (n=9), compared to the HCC (n=10) (P=0.002). Tumor size and PRETEXT stages were higher in hepatoblastoma patients; however, there was no statistical difference (P=0.06). Initial MRI was available for six patients with hepatoblastoma and seven patients with HCC, and there was no difference regarding ADCmin values. CONCLUSION In the differential diagnosis of primary malignant liver tumor in a child older than 5 years of age, higher sAFP level may support the diagnosis of hepatoblastoma rather than HCC.
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Affiliation(s)
- Gozde Ozer
- Hacettepe University School of Medicine, Department of Radiology, Sıhhiye, 06100, Ankara, Turkey.
| | - H Nursun Ozcan
- Hacettepe University School of Medicine, Department of Radiology, Sıhhiye, 06100, Ankara, Turkey
| | - Burak Ardicli
- Hacettepe University School of Medicine, Department of Radiology, Sıhhiye, 06100, Ankara, Turkey
| | - Tezer Kutluk
- Hacettepe University School of Medicine, Department of Radiology, Sıhhiye, 06100, Ankara, Turkey
| | - Berna Oguz
- Hacettepe University School of Medicine, Department of Radiology, Sıhhiye, 06100, Ankara, Turkey
| | - Mithat Haliloglu
- Hacettepe University School of Medicine, Department of Radiology, Sıhhiye, 06100, Ankara, Turkey
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He Y, An C, Dong K, Lyu Z, Qin S, Tan K, Hao X, Zhu C, Xiu W, Hu B, Xia N, Wang C, Dong Q. A Novel Visual Model for Predicting Prognosis of Resected Hepatoblastoma: A Multicenter Study. Acad Radiol 2025:S1076-6332(25)00197-7. [PMID: 40140274 DOI: 10.1016/j.acra.2025.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 02/26/2025] [Accepted: 03/02/2025] [Indexed: 03/28/2025]
Abstract
RATIONALE AND OBJECTIVES This study aimed to evaluate the application of a contrast-enhanced CT-based visual model in predicting postoperative prognosis in patients with hepatoblastoma (HB). MATERIALS AND METHODS We analyzed data from 224 patients across three centers (178 in the training cohort, 46 in the validation cohort). Visual features were extracted from contrast-enhanced CT images, and key features, along with clinicopathological data, were identified using LASSO Cox regression. Visual (DINOv2_score) and clinical (Clinical_score) models were developed, and a combined model integrating DINOv2_score and clinical risk factors was constructed. Nomograms were created for personalized risk assessment, with calibration curves and decision curve analysis (DCA) used to evaluate model performance. RESULTS The DINOv2_score was recognized as a key prognostic indicator for HB. In both the training and validation cohorts, the combined model demonstrated superior performance in predicting disease-free survival (DFS) [C-index (95% CI): 0.886 (0.879-0.895) and 0.873 (0.837-0.909), respectively] and overall survival (OS) [C-index (95% CI): 0.887 (0.877-0.897) and 0.882 (0.858-0.906), respectively]. Calibration curves showed strong alignment between predicted and observed outcomes, while DCA demonstrated that the combined model provided greater clinical net benefit than the clinical or visual models alone across a range of threshold probabilities. CONCLUSION The contrast-enhanced CT-based visual model serves as an effective tool for predicting postoperative prognosis in HB patients. The combined model, integrating the DINOv2_score and clinical risk factors, demonstrated superior performance in survival prediction, offering more precise guidance for personalized treatment strategies.
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Affiliation(s)
- Ying He
- Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao 266003, China (Y.H., X.H., W.X., C.W., Q.D.)
| | - Chaohui An
- Department of General Surgery, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (C.A., Z.L., K.T.)
| | - Kuiran Dong
- Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, China (K.D., S.Q.)
| | - Zhibao Lyu
- Department of General Surgery, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (C.A., Z.L., K.T.)
| | - Shanlu Qin
- Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, China (K.D., S.Q.)
| | - Kezhe Tan
- Department of General Surgery, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (C.A., Z.L., K.T.)
| | - Xiwei Hao
- Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao 266003, China (Y.H., X.H., W.X., C.W., Q.D.)
| | - Chengzhan Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao 266003, China (C.Z.)
| | - Wenli Xiu
- Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao 266003, China (Y.H., X.H., W.X., C.W., Q.D.)
| | - Bin Hu
- Department of Radiology, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao 266003, China (B.H.)
| | - Nan Xia
- Shandong Key Laboratory of Digital Medicine and Computer-Assisted Surgery, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266003, China (N.X.)
| | - Chaojin Wang
- Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao 266003, China (Y.H., X.H., W.X., C.W., Q.D.)
| | - Qian Dong
- Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao 266003, China (Y.H., X.H., W.X., C.W., Q.D.).
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Ding M, Ma C, Lin Y, Fang H, Xu Y, Wang S, Chen Y, Zhou J, Gao H, Shan Y, Yang L, Sun H, Tang Y, Wu X, Zhu L, Zheng L, Assaraf YG, Zhou BBS, Gu S, Li H. Therapeutic targeting de novo purine biosynthesis driven by β-catenin-dependent PPAT upregulation in hepatoblastoma. Cell Death Dis 2025; 16:179. [PMID: 40097378 PMCID: PMC11914223 DOI: 10.1038/s41419-025-07502-6] [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: 09/06/2024] [Revised: 02/07/2025] [Accepted: 03/06/2025] [Indexed: 03/19/2025]
Abstract
De novo purine biosynthesis (DNPS) was previously shown to be aberrantly activated in many cancers. However, the activity of DNPS pathway and its underlying regulatory mechanism in hepatoblastoma (HB) remain poorly understood. Herein, we discovered that the expression of PPAT, the rate-limiting enzyme in DNPS, was markedly upregulated in HB, leading to an augmented purine flux via DNPS, thereby promoting both HB cell proliferation and migration. Furthermore, we found that activated mutant β-catenin, a dominant driver of HB, transcriptionally activated PPAT expression, hence stimulating DNPS and constituting a druggable metabolic vulnerability in HB. Consistently, pharmacological targeting using a DNPS inhibitor lometrexol or genetic repressing the enhanced DNPS markedly blocked HB progression in vitro and in vivo. Our findings suggest that HB patients harboring activated β-catenin mutations and consequent DNPS upregulation, may be treated efficaciously with DNPS enzyme inhibitors like lometrexol. These novel findings bear major therapeutic implications for targeted precision medicine of HB.
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Affiliation(s)
- Ming Ding
- Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
- Fujian Children's Hospital, Fujian Branch of Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Fuzhou, 350014, China
| | - Chunshuang Ma
- Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Yanyan Lin
- Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Houshun Fang
- Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Yan Xu
- Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Shuxuan Wang
- Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Yao Chen
- Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Jiquan Zhou
- Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Hongxiang Gao
- Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Yuhua Shan
- Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Liyuan Yang
- Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Huiying Sun
- Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Yabin Tang
- Department of Pharmacology and Chemical Biology, School of Basic Medicine and Shanghai Collaborative Innovation Center for Translational Medicine Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xiaoyu Wu
- Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Liang Zhu
- Department of Pharmacology and Chemical Biology, School of Basic Medicine and Shanghai Collaborative Innovation Center for Translational Medicine Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Liang Zheng
- Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
- Fujian Children's Hospital, Fujian Branch of Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Fuzhou, 350014, China
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Laboratory, Faculty of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel.
| | - Bin-Bing S Zhou
- Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
- Fujian Children's Hospital, Fujian Branch of Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Fuzhou, 350014, China.
- Department of Pharmacology and Chemical Biology, School of Basic Medicine and Shanghai Collaborative Innovation Center for Translational Medicine Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Song Gu
- Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
| | - Hui Li
- Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
- Fujian Children's Hospital, Fujian Branch of Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Fuzhou, 350014, China.
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Desterke C, Francés R, Monge C, Marchio A, Pineau P, Mata-Garrido J. Single-Cell RNA-Seq Analysis Links DNMT3B and PFKFB4 Transcriptional Profiles with Metastatic Traits in Hepatoblastoma. Biomolecules 2024; 14:1394. [PMID: 39595571 PMCID: PMC11591731 DOI: 10.3390/biom14111394] [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: 09/13/2024] [Revised: 10/29/2024] [Accepted: 10/30/2024] [Indexed: 11/28/2024] Open
Abstract
Hepatoblastoma is the most common primary liver cancer in children. Poor outcomes are primarily associated with patients who have distant metastases. Using the Mammalian Metabolic Enzyme Database, we investigated the overexpression of metabolic enzymes in hepatoblastoma tumors compared to noncancerous liver tissue in the GSE131329 transcriptome dataset. For the overexpressed enzymes, we applied ElasticNet machine learning to assess their predictive value for metastasis. A metabolic expression score was then computed from the significant enzymes and integrated into a clinical-biological logistic regression model. Forty-one overexpressed enzymes distinguished hepatoblastoma tumors from noncancerous liver tissues. Eighteen of these enzymes predicted metastasis status with an AUC of 0.90, demonstrating 85.7% sensitivity and 92.3% specificity. ElasticNet machine learning identified DNMT3B and PFKFB4 as key predictors of metastasis. Univariate analyses confirmed the significance of these enzymes, with respective p-values of 0.0058 and 0.0091. A metabolic score based on DNMT3B and PFKFB4 expression discriminated metastasis status and high-risk CHIC scores (p-value = 0.005). The metabolic score was more sensitive than the C1/C2 classifier in predicting metastasis (accuracy: 0.72 vs. 0.55). In a regression model integrating the metabolic score with epidemiological parameters (gender, age at diagnosis, histological type, and clinical PRETEXT stage), the metabolic score was confirmed as an independent adverse predictor of metastasis (p-value = 0.003, odds ratio: 2.12). This study identified the dual overexpression of PFKFB4 and DNMT3B in hepatoblastoma patients at risk of metastasis (high-risk CHIC classification). The combined tumor expression of DNMT3B and PFKFB4 was used to compute a metabolic score, which was validated as an independent predictor of metastatic status in hepatoblastoma.
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Affiliation(s)
- Christophe Desterke
- Faculté de Médecine du Kremlin Bicêtre, Université Paris-Sud, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France;
| | - Raquel Francés
- Energy & Memory, Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, 75006 Paris, France;
| | - Claudia Monge
- INSERM U993, Unité Organisation Nucléaire et Oncogenèse, Institut Pasteur, Université Paris Cité, 75015 Paris, France; (C.M.); (A.M.); (P.P.)
| | - Agnès Marchio
- INSERM U993, Unité Organisation Nucléaire et Oncogenèse, Institut Pasteur, Université Paris Cité, 75015 Paris, France; (C.M.); (A.M.); (P.P.)
| | - Pascal Pineau
- INSERM U993, Unité Organisation Nucléaire et Oncogenèse, Institut Pasteur, Université Paris Cité, 75015 Paris, France; (C.M.); (A.M.); (P.P.)
| | - Jorge Mata-Garrido
- INSERM U993, Unité Organisation Nucléaire et Oncogenèse, Institut Pasteur, Université Paris Cité, 75015 Paris, France; (C.M.); (A.M.); (P.P.)
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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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Espinoza AF, Kureti P, Patel RH, Do SL, Govindu SR, Armbruster BW, Urbicain M, Patel KR, Lopez-Terrada D, Vasudevan SA, Woodfield SE. An indocyanine green-based liquid biopsy test for circulating tumor cells for pediatric liver cancer. Hepatol Commun 2024; 8:e0435. [PMID: 38727682 PMCID: PMC11093570 DOI: 10.1097/hc9.0000000000000435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 02/05/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Hepatoblastoma and HCC are the most common malignant hepatocellular tumors seen in children. The aim of this study was to develop a liquid biopsy test for circulating tumor cells (CTCs) for these tumors that would be less invasive and provide real-time information about tumor response to therapy. METHODS For this test, we utilized indocyanine green (ICG), a far-red fluorescent dye used clinically to identify malignant liver cells during surgery. We assessed ICG accumulation in cell lines using fluorescence microscopy and flow cytometry. For our CTC test, we developed a panel of liver tumor-specific markers, including ICG, Glypican-3, and DAPI, and tested it with cell lines and noncancer control blood samples. We then used this panel to analyze whole-blood samples for CTC burden with a cohort of 15 patients with hepatoblastoma and HCC and correlated with patient characteristics and outcomes. RESULTS We showed that ICG accumulation is specific to liver cancer cells, compared to nonmalignant liver cells, non-liver solid tumor cells, and other nonmalignant cells, and can be used to identify liver tumor cells in a mixed population of cells. Experiments with the ICG/Glypican-3/DAPI panel showed that it specifically tagged malignant liver cells. Using patient samples, we found that CTC burden from sequential blood samples from the same patients mirrored the patients' responses to therapy. CONCLUSIONS Our novel ICG-based liquid biopsy test for CTCs can be used to specifically detect and quantify CTCs in the blood of pediatric patients with liver cancer.
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Affiliation(s)
- Andres F. Espinoza
- Pediatric Surgical Oncology Laboratory, Michael E. DeBakey Department of Surgery, Divisions of Pediatric Surgery and Surgical Research, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Pavan Kureti
- Pediatric Surgical Oncology Laboratory, Michael E. DeBakey Department of Surgery, Divisions of Pediatric Surgery and Surgical Research, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Roma H. Patel
- Pediatric Surgical Oncology Laboratory, Michael E. DeBakey Department of Surgery, Divisions of Pediatric Surgery and Surgical Research, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Susan L. Do
- Pediatric Surgical Oncology Laboratory, Michael E. DeBakey Department of Surgery, Divisions of Pediatric Surgery and Surgical Research, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Saiabhiroop R. Govindu
- Pediatric Surgical Oncology Laboratory, Michael E. DeBakey Department of Surgery, Divisions of Pediatric Surgery and Surgical Research, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Bryan W. Armbruster
- Pediatric Surgical Oncology Laboratory, Michael E. DeBakey Department of Surgery, Divisions of Pediatric Surgery and Surgical Research, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Martin Urbicain
- Department of Pathology and Immunology, Baylor College of Medicine, Texas Children’s Department of Pathology, Houston, Texas, USA
| | - Kalyani R. Patel
- Department of Pathology and Immunology, Baylor College of Medicine, Texas Children’s Department of Pathology, Houston, Texas, USA
| | - Dolores Lopez-Terrada
- Department of Pathology and Immunology, Baylor College of Medicine, Texas Children’s Department of Pathology, Houston, Texas, USA
| | - Sanjeev A. Vasudevan
- Pediatric Surgical Oncology Laboratory, Michael E. DeBakey Department of Surgery, Divisions of Pediatric Surgery and Surgical Research, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Sarah E. Woodfield
- Pediatric Surgical Oncology Laboratory, Michael E. DeBakey Department of Surgery, Divisions of Pediatric Surgery and Surgical Research, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
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7
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Tang MJ, Ma XL, He XL, Pan WH, Zhang XH, Jiang SY, Gao J, Li F, Yao W, Gu S, Zhang WL, Zhao Q, Huang SH, Fang YJ, Liu W, Niu HZ, Wang CM, Sun LR, Gao H, Dai YP, Huang SG, Zhong ZY, Wang XG, Li ZR, Yang LC, Wu YM, Wang HM, Sun X, Yuan XJ. A multicenter prospective study on the management of hepatoblastoma in children: a report from the Chinese Children's Cancer Group. World J Pediatr 2024; 20:590-601. [PMID: 37770810 PMCID: PMC11239770 DOI: 10.1007/s12519-023-00750-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 07/17/2023] [Indexed: 09/30/2023]
Abstract
BACKGROUND This study aimed to identify survival risk factors in Chinese children with hepatoblastoma (HB) and assess the effectiveness of the new treatment protocol proposed by the Chinese Children's Cancer Group (CCCG) in 2016. METHODS A multicenter, prospective study that included 399 patients with HB from January 2015 to June 2020 was conducted. Patient demographics, treatment protocols, and other related information were collected. Cox regression models and Kaplan-Meier curve methods were used. RESULTS The 4-year event-free survival (EFS) and overall survival (OS) were 76.9 and 93.5%, respectively. The 4-year EFS rates for the very-low-risk, low-risk, intermediate-risk, and high-risk groups were 100%, 91.6%, 81.7%, and 51.0%, respectively. The 4-year OS was 100%, 97.3%, 94.4%, and 86.8%, respectively. Cox regression analysis found that age, tumor rupture (R +), and extrahepatic tumor extension (E +) were independent prognostic factors. A total of 299 patients had complete remission, and 19 relapsed. Patients with declining alpha-fetoprotein (AFP) > 75% after the first two cycles of neoadjuvant chemotherapy had a better EFS and OS than those ≤ 75%. CONCLUSIONS The survival outcome of HB children has dramatically improved since the implementation of CCCG-HB-2016 therapy. Age ≥ 8 years, R + , and E + were independent risk factors for prognosis. Patients with a declining AFP > 75% after the first two cycles of neoadjuvant chemotherapy had better EFS and OS.
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Affiliation(s)
- Meng-Jie Tang
- Department of Pediatric Hematology/Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Xiao-Li Ma
- Medical Oncology Department, Pediatric Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Xiang-Ling He
- Department of Hematology/Oncology, Children's Medical Center, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 41005, China
| | - Wei-Hua Pan
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Xiao-Hong Zhang
- Department of Hematology/Oncology, Guangzhou Women and Children's Medical Center, National Children's Medical Center for South Central Region, Guangzhou, 510623, China
| | - Sha-Yi Jiang
- Department of Hematology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, China
| | - Ju Gao
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
| | - Fu Li
- Department of Hematology/Oncology, Qilu Children's Hospital of Shandong University, Jinan, 250022, China
| | - Wei Yao
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Song Gu
- Department of General Surgery, Shanghai Children's Medical Center (National Children's Medical Center-Shanghai), Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Wei-Ling Zhang
- Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Qiang Zhao
- Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Shi-Hao Huang
- Department of Pediatric Hematology/Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Yong-Jun Fang
- Department of Hematology/Oncology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China
| | - Wei Liu
- Department of Hematology/Oncology, Henan Children's Hospital, Zhengzhou, 450018, China
| | - Hui-Zhong Niu
- Department of Pediatric General Surgery, Hebei Children's Hospital of Hebei Medical University, Shijiazhuang City, 050031, China
| | - Chun-Mei Wang
- Children's Hospital, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Li-Rong Sun
- Department of Paediatric Hematology/Oncology, the Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Hui Gao
- Department of Paediatric Hematology/Oncology, Dalian Women and Children's Medical Group, Dalian, 116037, China
| | - Yun-Peng Dai
- Department of Pediatric Hematology/Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Shun-Gen Huang
- Department of General Surgery, Children's Hospital of Soochow University, Suzhou, 215028, China
| | - Zhi-Yong Zhong
- Department of Pediatric Surgery, the Second Hospital of HeBei Medical University, Shijiazhuang, 050000, China
| | - Xi-Ge Wang
- Department of Paediatric Hematology/Oncology, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Zhong-Rong Li
- Department of Pediatric Surgery, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Liang-Chun Yang
- Department of Pediatrics, Xiangya Hospital Central South University, Changsha, 410008, China
| | - Ye-Ming Wu
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Huan-Min Wang
- Department of Surgical Oncology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China.
| | - Xin Sun
- Clinical Research and Innovation Unit, XinHua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
| | - Xiao-Jun Yuan
- Department of Pediatric Hematology/Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China.
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8
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Xiang X, Hao Y, Cheng C, Hu H, Chen H, Tan J, Wang Y, Liu X, Peng B, Liao J, Wang J, Xie Y, Liu J, Chen S, Xu L, Xie W, Xue R, Kuang M, Xu Z, Jiang H, Peng S. A TGF-β-dominant chemoresistant phenotype of hepatoblastoma associated with aflatoxin exposure in children. Hepatology 2024; 79:650-665. [PMID: 37459556 DOI: 10.1097/hep.0000000000000534] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 07/03/2023] [Indexed: 02/18/2024]
Abstract
BACKGROUND AND AIMS Hepatoblastoma (HB) is the most common liver cancer in children, posing a serious threat to children's health. Chemoresistance is the leading cause of mortality in patients with HB. A more explicit definition of the features of chemotherapy resistance in HB represents a fundamental urgent need. APPROACH AND RESULTS We performed an integrative analysis including single-cell RNA sequencing, whole-exome sequencing, and bulk RNA sequencing in 180 HB samples, to reveal genomic features, transcriptomic profiles, and the immune microenvironment of HB. Multicolor immunohistochemistry staining and in vitro experiments were performed for validation. Here, we reported four HB transcriptional subtypes primarily defined by differential expression of transcription factors. Among them, the S2A subtype, characterized by strong expression of progenitor ( MYCN , MIXL1 ) and mesenchymal transcription factors ( TWIST1 , TBX5 ), was defined as a new chemoresistant subtype. The S2A subtype showed increased TGF-β cancer-associated fibroblast and an immunosuppressive microenvironment induced by the upregulated TGF-β of HB. Interestingly, the S2A subtype enriched SBS24 signature and significantly higher serum aflatoxin B1-albumin (AFB1-ALB) level in comparison with other subtypes. Functional assays indicated that aflatoxin promotes HB to upregulate TGF-β. Furthermore, clinical prognostic analysis showed that serum AFB1-ALB is a potential indicator of HB chemoresistance and prognosis. CONCLUSIONS Our studies offer new insights into the relationship between aflatoxin and HB chemoresistance and provide important implications for its diagnosis and treatment.
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Affiliation(s)
- Xiao Xiang
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yijie Hao
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Cheng Cheng
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Huanjing Hu
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Huadong Chen
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jiehui Tan
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yuanqi Wang
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaofei Liu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Bo Peng
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Junbin Liao
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ji Wang
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yubin Xie
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Juncheng Liu
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Shuling Chen
- Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Lixia Xu
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wenxuan Xie
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ruidong Xue
- Peking University First Hospital, Translational Cancer Research, Beijing, China
| | - Ming Kuang
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Sun Yat-sen University Zhongshan School of Medicine, Guangzhou, China
| | - Zhe Xu
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Hong Jiang
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Sui Peng
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Clinical Trial Unit, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 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: 0] [Impact Index Per Article: 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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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-Like Lesions. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:842-946. [DOI: 10.1016/b978-0-7020-8228-3.00013-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Bhagat P, Vij M, Raju LP, Gowrishankar G, Menon J, Shanmugam N, Kaliamoorthy I, Rammohan A, Rela M. Update on the Pathology of Pediatric Liver Tumors: A Pictorial Review. Diagnostics (Basel) 2023; 13:3524. [PMID: 38066766 PMCID: PMC10706829 DOI: 10.3390/diagnostics13233524] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/18/2023] [Accepted: 11/20/2023] [Indexed: 01/04/2025] Open
Abstract
Liver tumors in children are uncommon and show remarkable morphologic heterogeneity. Pediatric tumors may arise from either the epithelial or mesenchymal component of the liver and rarely may also show both lines of differentiation. Both benign and malignant liver tumors have been reported in children. The most common pediatric liver tumors by age are benign hepatic infantile hemangiomas in neonates and infants, malignant hepatoblastoma in infants and toddlers, and malignant hepatocellular carcinoma in teenagers. Here, we provide an up-to-date review of pediatric liver tumors. We discuss the clinical presentation, imaging findings, pathology, and relevant molecular features that can help in the correct identification of these tumors, which is important in managing these children.
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Affiliation(s)
- Priyanka Bhagat
- Department of Pathology, Choithram Hospital and Research Center, Manik Bagh Road, Indore 452014, Madhya Pradesh, India;
| | - Mukul Vij
- Department of Pathology, Dr. Rela Institute & Medical Centre, No. 7 CLC Works Road Chromepet, Chennai 600044, Tamil Nadu, India; (L.P.R.); (G.G.)
| | - Lexmi Priya Raju
- Department of Pathology, Dr. Rela Institute & Medical Centre, No. 7 CLC Works Road Chromepet, Chennai 600044, Tamil Nadu, India; (L.P.R.); (G.G.)
| | - Gowripriya Gowrishankar
- Department of Pathology, Dr. Rela Institute & Medical Centre, No. 7 CLC Works Road Chromepet, Chennai 600044, Tamil Nadu, India; (L.P.R.); (G.G.)
| | - Jagadeesh Menon
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, No. 7 CLC Works Road Chromepet, Chennai 600044, Tamil Nadu, India; (J.M.); (N.S.); (I.K.); (A.R.); (M.R.)
| | - Naresh Shanmugam
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, No. 7 CLC Works Road Chromepet, Chennai 600044, Tamil Nadu, India; (J.M.); (N.S.); (I.K.); (A.R.); (M.R.)
| | - Ilankumaran Kaliamoorthy
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, No. 7 CLC Works Road Chromepet, Chennai 600044, Tamil Nadu, India; (J.M.); (N.S.); (I.K.); (A.R.); (M.R.)
| | - Ashwin Rammohan
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, No. 7 CLC Works Road Chromepet, Chennai 600044, Tamil Nadu, India; (J.M.); (N.S.); (I.K.); (A.R.); (M.R.)
| | - Mohamed Rela
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, No. 7 CLC Works Road Chromepet, Chennai 600044, Tamil Nadu, India; (J.M.); (N.S.); (I.K.); (A.R.); (M.R.)
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12
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Zheng C, Ye S, Liu W, Diao M, Li L. Prognostic value of systemic inflammation response index in hepatoblastoma patients receiving preoperative neoadjuvant chemotherapy. Front Oncol 2023; 13:1276175. [PMID: 37901310 PMCID: PMC10613067 DOI: 10.3389/fonc.2023.1276175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 10/02/2023] [Indexed: 10/31/2023] Open
Abstract
Introduction Inflammation is closely associated with tumor development and patient prognosis. The objective of this study is to assess the prognostic value of the preoperative inflammatory indexes in pediatric hepatoblastoma patients who receive neoadjuvant chemotherapy. Methods A retrospective analysis was performed on clinical and pathological data of 199 hepatoblastoma patients who underwent hepatectomy with preoperative neoadjuvant chemotherapy from January 2015 to June 2020. The receiver operating characteristic curve was used to evaluate the prognostic value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI) in predicting OS and EFS. Patients were grouped based on optimal cutoff values of preoperative inflammatory indexes. Survival rates were calculated using the Kaplan-Meier method, and survival outcomes were compared between groups using the log-rank test. Univariate and multivariate Cox proportional hazards regression models were used to identify independent prognostic factors, and a nomogram was constructed using R software to predict the probability of OS. Results The receiver operating characteristic curve showed prognostic value for OS, not EFS, in preoperative inflammatory indexes. Patients were categorized into low/high groups: SII ≤ 266.70/higher, NLR ≤ 1.24/higher, PLR ≤ 85.25/higher, and SIRI ≤ 0.72/higher. High NLR, PLR, SII, and SIRI groups had significantly lower 5-year OS than their low counterparts (all p-value < 0.05). The Cox analysis identified four independent prognostic factors: SIRI (HR=2.997, 95% CI: 1.119-8.031), microvascular invasion (HR=2.556, 95% CI: 1.14-5.73), the post-treatment extent of disease (POSTTEXT) staging (IV vs. I: HR=244.204, 95% CI:11.306-5274.556), and alpha-fetoprotein (>100 ng/ml: HR=0.11, 95% CI: 0.032-0.381) for hepatoblastoma patients with neoadjuvant chemotherapy. High SIRI group had more patients with adverse NLR, SII, and POSTTEXT III (all p-value < 0.05). Independent prognostic factors led to an OS nomogram with a concordance index of 0.85 (95% CI: 0.78-0.91, p-value = 1.43e-27) and the calibration curve showed a good fit between the prediction curve and the true curve. Conclusions SIRI is an independent prognostic factor of hepatoblastoma patients receiving neoadjuvant chemotherapy. The OS nomogram based on SIRI, POSTTEXT staging, MiVI, and AFP can be used to assess the prognosis of those patients.
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Affiliation(s)
- Chen Zheng
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Research Unit of Minimally Invasive Pediatric Surgery on Diagnosis and Treatment, Chinese Academy of Medical Sciences, Beijing, China
| | - Shiru Ye
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, China
| | - Wei Liu
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Research Unit of Minimally Invasive Pediatric Surgery on Diagnosis and Treatment, Chinese Academy of Medical Sciences, Beijing, China
| | - Mei Diao
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Research Unit of Minimally Invasive Pediatric Surgery on Diagnosis and Treatment, Chinese Academy of Medical Sciences, Beijing, China
| | - Long Li
- Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Research Unit of Minimally Invasive Pediatric Surgery on Diagnosis and Treatment, Chinese Academy of Medical Sciences, Beijing, China
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13
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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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Espinoza AF, Kureti P, Patel RH, Govindu SR, Armbruster BW, Urbicain M, Patel KR, Lopez-Terrada D, Vasudevan SA, Woodfield SE. An indocyanine green-based liquid biopsy test for circulating tumor cells for pediatric liver cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.03.547557. [PMID: 37461615 PMCID: PMC10349946 DOI: 10.1101/2023.07.03.547557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Background and Aims Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the most common malignant hepatocellular tumors seen in children. The aim of this work was to develop a liquid biopsy test for circulating tumor cells (CTCs) for these tumors that would be less invasive and provide information about the real-time state of tumors in response to therapies. Methods For this test, we utilized indocyanine green (ICG), a far-red fluorescent dye that is used clinically to identify malignant liver cells in the body during surgery. We assessed ICG accumulation in cell lines with fluorescence microscopy and flow cytometry. For our CTC test, we developed a panel of liver tumor-specific markers, ICG, Glypican-3 (GPC3), and DAPI and tested this panel with cell lines and non-cancer control blood samples. We then used this panel to analyze whole blood samples for CTC burden with a cohort of 14 HB and HCC patients and correlated with patient characteristics and outcomes. Results We showed that ICG accumulation is specific to liver cancer cells, compared to non-malignant liver cells, non-liver solid tumor cells, and non-malignant cells and can be used to identify liver tumor cells in a mixed population of cells. Experiments with the ICG/GPC3/DAPI panel showed that it specifically tagged malignant liver cells. With patient samples, we found that CTC burden from sequential blood samples from the same patients mirrored the patients' responses to therapy. Conclusions Our novel ICG-based liquid biopsy test for CTCs can be used to specifically count CTCs in the blood of pediatric liver cancer patients. Impact and implications This manuscript represents the first report of circulating tumor cells in the blood of pediatric liver cancer patients. The novel and innovative assay for CTCs shown in this paper will facilitate future work examining the relationship between CTC numbers and patient outcomes, forming the foundation for incorporation of liquid biopsy into routine clinical care for these patients. Graphical abstract Overview of novel liquid biopsy test for circulating tumor cells for pediatric liver cancer. Figure made with Biorender.
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15
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Cho SJ, Ranganathan S, Alaggio R, Maibach R, Tanaka Y, Inoue T, Leuschner I, de Krijger R, Vokuhl C, Krailo M, Malogolowkin M, Meyers R, Czauderna P, Hiyama E, Ansari M, Morland B, Trobaugh-Lotrario A, O'Neill AF, Rangaswami A, Häberle B, López-Terrada D. Consensus classification of pediatric hepatocellular tumors: A report from the Children's Hepatic tumors International Collaboration (CHIC). Pediatr Blood Cancer 2023:e30505. [PMID: 37384428 DOI: 10.1002/pbc.30505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 05/15/2023] [Accepted: 06/02/2023] [Indexed: 07/01/2023]
Abstract
BACKGROUND Liver tumors are rare in children with histologic heterogeneity that makes diagnosis challenging. Systematic histopathological review, performed as part of collaborative therapeutic protocols, identified relevant histologic subtypes that are important to distinguish. The Children's Hepatic tumors International Collaboration (CHIC) was established to study pediatric liver tumors on a global scale and led to establishment of a provisional consensus classification for use in international clinical trials. The current study is the validation of this initial classification and first large-scale application by international expert reviewers. PROCEDURE The CHIC initiative includes data from 1605 children treated on eight multicenter hepatoblastoma (HB) trials. Review of 605 available tumors was performed by seven expert pathologists from three consortia (US, EU, Japan). Cases with discordant diagnoses were collectively reviewed to reach a final consensus diagnosis. RESULTS Of 599 cases with sufficient material for review, 570 (95.2%) were classified as HB by all consortia, and 29 (4.8%) as non-HB, which included "hepatocellular neoplasm, NOS" and malignant rhabdoid tumors. 453 of 570 HBs were classified as epithelial by final consensus. Some patterns (i.e., small cell undifferentiated, macrotrabecular, cholangioblastic) were selectively identified by reviewers from different consortia. All consortia identified a similar number of mixed epithelial-mesenchymal HB. CONCLUSIONS This study represents the first large-scale application and validation of the pediatric malignant hepatocellular tumors consensus classification. It is a valuable resource to train future generations of investigators on accurate diagnosis of these rare tumors and provides a framework for further international collaborative studies and refinement of the current classification of pediatric liver tumors.
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Affiliation(s)
- Soo-Jin Cho
- Department of Pathology, University of California San Francisco, San Francisco, California, USA
| | - Sarangarajan Ranganathan
- Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Rita Alaggio
- Department of Pathology, Bambino Gesu Pediatric Hospital, Roma, Italy
| | | | - Yukichi Tanaka
- Department of Pathology, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Takeshi Inoue
- Department of Pathology, Osaka City General Hospital, Osaka, Japan
| | - Ivo Leuschner
- UNI-Klinikum Campus, Institut fur Pathologie, Kiel, Germany
| | - Ronald de Krijger
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Christian Vokuhl
- Section of Pediatric Pathology, Department of Pathology, University Hospital Bonn, Bonn, Germany
| | - Mark Krailo
- Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA
| | - Marcio Malogolowkin
- Division of Pediatric Hematology Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, California, USA
| | - Rebecka Meyers
- Division of Pediatric Surgery, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Piotr Czauderna
- Department of Surgery and Urology for Children and Adolescents, Medical University of Gdansk, Gdansk, Poland
| | - Eiso Hiyama
- Department of Pediatric Surgery, Hiroshima University, Hiroshima, Japan
| | - Marc Ansari
- Division of Pediatric Oncology and Hematology, Department of Women, Child and Adolescent, University Geneva Hospitals, Geneva, Switzerland
- Faculty of Medicine, Department of Pediatrics Cansearch Research Platform for Pediatric Oncology and Hematology, Gynecology and Obstetrics, University of Geneva, Geneva, Switzerland
| | - Bruce Morland
- Department of Oncology, Birmingham Women's and Children's Hospital, Birmingham, UK
| | - Angela Trobaugh-Lotrario
- Department of Pediatric Hematology/Oncology, Providence Sacred Heart Children's Hospital, Spokane, Washington, USA
| | - Allison F O'Neill
- Department of Pediatric Oncology, Dana-Farber Cancer Institute/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Arun Rangaswami
- Division of Pediatric Hematology and Oncology, University of California San Francisco, San Francisco, California, USA
| | - Beate Häberle
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Dolores López-Terrada
- Department of Pathology and Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA
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16
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Patil Okaly GV, Prakash A, Akshatha C, Nargund A, Cherian LB, Balu S, Arun Kumar AR. A Clinicopathological Study with Risk-Stratified Staging of Pediatric Hepatoblastoma: A 5-Year Experience from a Tertiary Cancer Center. IRANIAN JOURNAL OF PATHOLOGY 2023; 18:165-172. [PMID: 37600579 PMCID: PMC10439754 DOI: 10.30699/ijp.2023.1972340.3005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 01/12/2023] [Indexed: 08/22/2023]
Abstract
Background & Objective Hepatoblastoma encompasses 1% of pediatric malignancies and is the most common liver malignancy in children. Ninety percent of cases are younger than 5 years of age. Clinical and pathological risk stratification forms a crucial role in determining the treatment strategy. This study aimed to assess the clinicopathological profile of hepatoblastoma with risk stratification and follow-up in children. Methods A retrospective evaluation was performed on all pediatric patients diagnosed as hepatoblastoma between 2016 and 2020 in our institution. Clinical, radiological, biochemical, pathological, and treatment data were analyzed. Cases were stratified based on the SIOPEL protocol and compared with the outcome. Results The median age of all children was 1 year, the male-to-female ratio was 2.3:1, and elevated α-fetoprotein (AFP) was observed in all cases. SIOPEL risk stratification showed that 50% of children were at high risk. The histopathological types were fetal (30%), embryonal (20%), and macrotrabecular (5%) patterns under epithelial type and mixed epithelial and mesenchymal type (45%) with 1 case showing teratoid features. During the follow-up period, 6 out of the 7 children who died, belonged to the high-risk SIOPEL category, and 5 presented a mixed epithelial and mesenchymal pattern. Conclusion Our study found a significant correlation between clinicopathological data, histopathological patterns, and outcomes. Accordingly, histopathological patterns could be considered one of the criteria for risk stratification. Histopathological risk stratification indicators (such as SIOPEL and PRETEXT) have strong prognostic and predictive outcomes; hence, our study emphasizes such parameters to aid oncologists.
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Affiliation(s)
- Geeta V Patil Okaly
- Department of Pathology, Kidwai Memorial Institute of Oncology, Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka, India
| | - Akina Prakash
- Department of Pathology, Kidwai Memorial Institute of Oncology, Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka, India
| | - C Akshatha
- Department of Pathology, Kidwai Memorial Institute of Oncology, Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka, India
| | - Ashwini Nargund
- Department of Pathology, Kidwai Memorial Institute of Oncology, Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka, India
| | - Libin Babu Cherian
- Department of Pathology, Kidwai Memorial Institute of Oncology, Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka, India
| | - S Balu
- Department of Pathology, Kidwai Memorial Institute of Oncology, Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka, India
| | - AR Arun Kumar
- Department of Pediatric Oncology, Kidwai Memorial Institute of Oncology, Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka, India
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17
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Schooler GR, Infante JC, Acord M, Alazraki A, Chavhan GB, Davis JC, Khanna G, Morani AC, Morin CE, Nguyen HN, Rees MA, Shaikh R, Srinivasan A, Squires JH, Tang E, Thacker PG, Towbin AJ. Imaging of pediatric liver tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper. Pediatr Blood Cancer 2023; 70 Suppl 4:e29965. [PMID: 36102690 PMCID: PMC10641897 DOI: 10.1002/pbc.29965] [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: 08/05/2022] [Accepted: 08/16/2022] [Indexed: 11/11/2022]
Abstract
Primary hepatic malignancies are relatively rare in the pediatric population, accounting for approximately 1%-2% of all pediatric tumors. Hepatoblastoma and hepatocellular carcinoma are the most common primary liver malignancies in children under the age of 5 years and over the age of 10 years, respectively. This paper provides consensus-based imaging recommendations for evaluation of patients with primary hepatic malignancies at diagnosis and follow-up during and after therapy.
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Affiliation(s)
- Gary R. Schooler
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX
| | - Juan C. Infante
- Department of Radiology, Nemours Children’s Health, Orlando, FL
| | - Michael Acord
- Department of Radiology, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Adina Alazraki
- Department of Radiology and Imaging Sciences, Emory University, Children’s Healthcare of Atlanta, Atlanta, GA
| | - Govind B. Chavhan
- Department of Diagnostic Imaging, Hospital for Sick Children and Department of Medical Imaging, University of Toronto, ON Canada
| | | | - Geetika Khanna
- Department of Radiology and Imaging Sciences, Emory University, Children’s Healthcare of Atlanta, Atlanta, GA
| | - Ajaykumar C. Morani
- Singleton Department of Radiology, Texas Children’s Hospital and Department of Radiology, Baylor College of Medicine, Houston, TX
| | - Cara E. Morin
- Department of Radiology, Cincinnati Children’s Hospital, Cincinnati, OH
| | - HaiThuy N. Nguyen
- Singleton Department of Radiology, Texas Children’s Hospital and Department of Radiology, Baylor College of Medicine, Houston, TX
| | - Mitchell A. Rees
- Department of Radiology, Nationwide Children’s Hospital, Columbus, OH
| | - Raja Shaikh
- Department of Radiology, Boston Children’s Hospital, Boston, MA
| | - Abhay Srinivasan
- Department of Radiology, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Judy H. Squires
- Department of Radiology, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA
| | - Elizabeth Tang
- Department of Radiology, Seattle Children’s Hospital, Seattle, WA
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Honda M, Uchida K, Irie T, Hirukawa K, Kadohisa M, Shimata K, Isono K, Shimojima N, Sugawara Y, Hibi T. Recent advances in surgical strategies and liver transplantation for hepatoblastoma. Cancer Med 2023; 12:3909-3918. [PMID: 36394165 PMCID: PMC9972171 DOI: 10.1002/cam4.5300] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/22/2022] [Accepted: 09/15/2022] [Indexed: 11/18/2022] Open
Abstract
Hepatoblastoma (HB) is the most common malignant liver tumor in children. Although the development of treatment strategies with advances in chemotherapy has greatly improved the prognosis of HB, surgical resection and liver transplantation still play a vital role in the treatment of HB. In recent years, technological innovations have led to the development of new surgical approaches for HB. In this review, we describe the latest research on the surgical management of HB, including new imaging technologies, minimally invasive approaches, and the application of associating liver partition portal vein ligation for staged hepatectomy. We also discuss the current role of liver transplantation, use of ante-situm or ex-situ liver resection with auto-transplantation, and management of metastatic HB.
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Affiliation(s)
- Masaki Honda
- Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - Koushi Uchida
- Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - Tomoaki Irie
- Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - Kazuya Hirukawa
- Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - Masashi Kadohisa
- Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - Keita Shimata
- Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - Kaori Isono
- Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - Naoki Shimojima
- Department of Surgery, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan
| | - Yasuhiko Sugawara
- Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - Taizo Hibi
- Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
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19
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Upregulation of SERPINE2 Results in Poor Prognosis of Hepatoblastoma via Promoting Invasion Abilities. DISEASE MARKERS 2022; 2022:2283541. [PMID: 36505099 PMCID: PMC9734000 DOI: 10.1155/2022/2283541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 11/08/2022] [Accepted: 11/10/2022] [Indexed: 12/04/2022]
Abstract
Background Hepatoblastoma (HB) is the most common malignant liver tumor in children. High-risk patients, especially those with tumor metastasis, have poor prognosis. Serpin family E member 2 (SERPINE2) is overexpressed in a variety of tumors, especially adenocarcinoma, and promotes tumor invasion and metastasis. The function and mechanism of SERPINE2 in HB are still unclear. The purpose of this study was to investigate the potential clinical prognostic value and molecular mechanism of SERPINE2 in HB. Methods We performed bioinformatics analyses on HB microarray data GSE131329 to study the role of SERPINE2. The expression level of SERPINE2 in HB and its clinical significance were further analyzed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemistry. After constructing the SERPINE2 overexpression and knockdown in HepG2 and HUH6 cells, the 5-ethynyl-29-deoxyuridine (EdU) assay, wound healing assay, Transwell experiment, and apoptosis assay were performed to explore the role of SERPINE2 in HB progress. Results Upregulation of SERPINE2 was found in HB tissues and was associated with a poor prognosis. Moreover, the SERPINE2 expression was related to tumor size, vascular invasion, and tumor metastasis. The Cox regressions show that high SERPINE2 expression is an independent risk factor for HB. SERPINE2 overexpression remarkably enhanced HB cell migration and invasion and suppressed apoptosis, while knockdown of SERPINE2 exerted the opposite effect. In addition, SERPINE2 facilitated the epithelial to mesenchymal transformation (EMT) phenotype of HB cells in vitro. Conclusion Our findings indicated that SERPINE2 accelerates HB progression, suggesting that SERPINE2 may be a potential prognostic biomarker and an underlying therapeutic target for HB.
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20
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Gong W, Han Z, Fang F, Chen L. Yap Expression Is Closely Related to Tumor Angiogenesis and Poor Prognosis in Hepatoblastoma. Fetal Pediatr Pathol 2022; 41:929-939. [PMID: 34978260 DOI: 10.1080/15513815.2021.2020384] [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] [Indexed: 11/04/2022]
Abstract
Background: Hepatoblastoma (HB) is malignant embryonal tumor typically arising in infants and young children. Yes-associated protein (YAP) is aberrantly activated in various tumors; however, the role of YAP in hepatoblastoma is still unexplored. Methods: We assessed YAP expression in hepatoblastoma using immunohistochemistry. The relationships to clinicopathology and survival were analyzed. Results: Positive rate of YAP expression was higher in hepatoblastoma than in adjacent tissues. YAP overexpression was significantly correlated with lymph node metastasis and vascular invasion. Both epithelial and mixed histological types expressed YAP, but high expression was more frequent in MT. YAP expression correlated with VEGF expression, high microvascular density and low overall survival. Multivariable Cox regression analysis revealed that YAP was an independent prognostic factor for survival in children with hepatoblastoma. Conclusion: In hepatoblastoma, YAP may promote VEGF induced angiogenesis and metastases, with resulting poorer prognosis, representing a potential adverse prognostic marker.
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Affiliation(s)
- Wenchen Gong
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Zhiqiang Han
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Feng Fang
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Lu Chen
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
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21
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Tayfun Küpesiz F, Akınel AN, Akbaş H, Sivrice Ç, Tüysüz Kintrup G, Karagüzel G, Melikoğlu M, Gelen MT, Aydınlı B, Küpesiz A, Güler E. Multidisciplinary Management of Pediatric Hepatoblastoma: A 20-Year Single-Center Experience. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2022; 33:1069-1078. [PMID: 36262102 PMCID: PMC9797744 DOI: 10.5152/tjg.2022.21827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Hepatoblastoma is rare cancer that responds well to risk-based chemotherapy, and surgical treatment is needed to achieve complete remission and satisfactory survival rates in hepatoblastoma patients. In this study, we evaluated the clinical features and treatment outcomes of pediatric hepatoblastoma patients treated in our clinic. METHODS Eighteen patients with hepatoblastoma who were treated and followed up in our center between June 1999 and June 2020 were analyzed retrospectively. All patients were evaluated by a multidisciplinary team and managed using a risk-based protocol (SIOPEL-1 and SIOPEL-3). RESULTS The patients' mean age at diagnosis was 38.33 ± 52.34 months. Sixteen patients (89%) received neoadjuvant chemotherapy, and 2 patients (11%) who underwent complete mass excision at diagnosis received adjuvant chemotherapy. After neoadjuvant therapy, the tumor was completely resected in 8 patients (45%), while liver transplantation was performed in 6 patients (34%) because complete resection of the tumor was not possible. Two patients died before surgical treatment. One patient relapsed with lung metastasis after salvage chemotherapy. She is alive without disease at 64 months. The mean follow-up time was 59.3 ± 49.8 months; 5-year overall and disease-free survival rates were 88.9% and 80.8%, respectively. The 5-year overall survival rate was 100% for both liver transplant and resected patients, whereas 5-year disease-free survival was lower in transplant patients (75% vs 100%, P < .001). CONCLUSION Multidisciplinary follow-up is especially important for patients who may need liver transplantation. Some patients may benefit from new treatment options such as radiofrequency ablation and cyberknife treatment.
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Affiliation(s)
- Funda Tayfun Küpesiz
- Division of Pediatric Hematology, Oncology and BMT, Department of Pediatrics, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Ayşe Nur Akınel
- Division of Pediatric Hematology, Oncology and BMT, Department of Pediatrics, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Hilal Akbaş
- Department of Hematology-Oncology, Clinic of Pediatrics, Konya City Hospital, Konya, Turkey
| | - Çiğdem Sivrice
- Division of Pediatric Hematology, Oncology and BMT, Department of Pediatrics, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Gülen Tüysüz Kintrup
- Division of Pediatric Hematology, Oncology and BMT, Department of Pediatrics, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Güngör Karagüzel
- Department of Pediatric Surgery, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Mustafa Melikoğlu
- Department of Pediatric Surgery, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | | | - Bülent Aydınlı
- Division of Organ Transplantation, Department of General Surgery, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Alphan Küpesiz
- Division of Pediatric Hematology, Oncology and BMT, Department of Pediatrics, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Elif Güler
- Division of Pediatric Hematology, Oncology and BMT, Department of Pediatrics, Akdeniz University Faculty of Medicine, Antalya, Turkey,Corresponding author: Elif Güler, e-mail:
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22
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Ke M, Zhou Y, Chang-Zhen Y, Li L, Diao M. A nomogram model to predict prognosis of patients with hepatoblastoma. Pediatr Blood Cancer 2022; 69:e29932. [PMID: 36031721 DOI: 10.1002/pbc.29932] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 07/22/2022] [Accepted: 07/29/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND Hepatoblastomas (HBs) are malignant liver tumors that most commonly develop in pediatric patients. Microvascular invasion may be a prognosis factor for patients with HBs. This study aimed to construct a model to predict the survival outcome in HBs. METHODS We retrospectively analyzed the clinical data of 311 patients with HBs who underwent surgical resection at our institution between June 2014 and August 2021. First, patients were divided into two groups: those who had pathologic microvascular invasion (n = 146) and those who did not (n = 165). Propensity score-matched (PSM) analysis was carried out between the two groups. The preoperative parameters and overall survival (OS) rate were compared between the two groups. Second, all 311 patients were randomly divided into the training and validation cohort in a ratio of 4:1. A nomogram was created in the training cohort to visualize the prediction of OS. Moreover, the validation cohort was used for validation. RESULTS Multivariate analysis suggested that age, histology type, microvascular invasion, multifocality, distant metastasis, and macrovascular involvement are independent prognostic factors for HBs. The nomogram showed good predictive ability in the training and validation cohorts with a C-index of 0.878 (95% CI, 0.831-0.925) and 0.847 (95% CI, 0.757-0.937), respectively. The calibration curve indicated good agreement between the prediction and observation for one-, two-, and three-year OS probabilities. CONCLUSION By combining preoperative imaging results and other clinical data, we established a nomogram to predict OS probability for patients with HB, which could be a potential tool to guide personalized treatment.
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Affiliation(s)
- Meng Ke
- 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
| | - Yan Zhou
- 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
| | - Yang Chang-Zhen
- 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.,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.,Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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Fan L, Pan Q, Yang W, Koo SC, Tian C, Li L, Lu M, Brown A, Ju B, Easton J, Ranganathan S, Shin S, Bondoc A, Yang JJ, Yu J, Zhu L. A developmentally prometastatic niche to hepatoblastoma in neonatal liver mediated by the Cxcl1/Cxcr2 axis. Hepatology 2022; 76:1275-1290. [PMID: 35179799 PMCID: PMC9385889 DOI: 10.1002/hep.32412] [Citation(s) in RCA: 6] [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: 10/28/2021] [Revised: 02/15/2022] [Accepted: 02/15/2022] [Indexed: 12/08/2022]
Abstract
BACKGROUND AND AIMS Hepatoblastoma (HB) is the most common pediatric liver cancer. Its predominant occurrence in very young children led us to investigate whether the neonatal liver provides a protumorigenic niche to HB development. APPROACH AND RESULTS HB development was compared between orthotopic transplantation models established in postnatal day 5 (P5) and 60 (P60) mice (P5Tx and P60Tx models). Single-cell RNA-sequencing (sc-RNAseq) was performed using tumor and liver tissues from both models and the top candidate cell types and genes identified are investigated for their roles in HB cell growth, migration, and survival. CONCLUSIONS We found that various HB cell lines including HepG2 cells were consistently and considerably more tumorigenic and metastatic in the P5Tx model than in the P60Tx models. Sc-RNAseq of the P5Tx and P60Tx HepG2 models revealed that the P5Tx tumor was more hypoxic and had a larger number of activated hepatic stellate cells (aHSCs) in the tumor-surrounding liver that express significantly higher levels of Cxcl1 than those from the P60Tx model. We found these differences were developmentally present in normal P5 and P60 liver. We showed that the Cxcl1/Cxcr2 axis mediated HB cell migration and was critical to HB cell survival under hypoxia. Treating HepG2 P60Tx model with recombinant CXCL1 protein induced intrahepatic and pulmonary metastasis and CXCR2 knockout (KO) in HepG2 cells abolished their metastatic potential in the P5Tx model. Lastly, we showed that in tumors from patients with metastatic HB, there was a similar larger population of aHSCs in the tumor-surrounding liver than in localized tumors, and tumor hypoxia was uniquely associated with prognosis of patients with HB among pediatric cancers. We demonstrated that the neonatal liver provides a prometastatic niche to HB development through the Cxcl1/Cxcr2 axis.
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Affiliation(s)
- Li Fan
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States
| | - Qingfei Pan
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States
| | - Wentao Yang
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States
| | - Selene C. Koo
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States
| | - Cheng Tian
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States
| | - Liyuan Li
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States
| | - Meifen Lu
- Veterinary Pathology Core, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States
| | - Anthony Brown
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States
| | - Bensheng Ju
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States
| | - John Easton
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States
| | - Sarangarajan Ranganathan
- Department of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital, Cincinnati, Ohio, United States
| | - Soona Shin
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
| | - Alexander Bondoc
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
| | - Jun J. Yang
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States
| | - Jiyang Yu
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States
| | - Liqin Zhu
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States
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24
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Song H, Bucher S, Rosenberg K, Tsui M, Burhan D, Hoffman D, Cho SJ, Rangaswami A, Breese M, Leung S, Ventura MVP, Sweet-Cordero EA, Huang FW, Nijagal A, Wang B. Single-cell analysis of hepatoblastoma identifies tumor signatures that predict chemotherapy susceptibility using patient-specific tumor spheroids. Nat Commun 2022; 13:4878. [PMID: 36008377 PMCID: PMC9411569 DOI: 10.1038/s41467-022-32473-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 08/02/2022] [Indexed: 11/22/2022] Open
Abstract
Pediatric hepatoblastoma is the most common primary liver cancer in infants and children. Studies of hepatoblastoma that focus exclusively on tumor cells demonstrate sparse somatic mutations and a common cell of origin, the hepatoblast, across patients. In contrast to the homogeneity these studies would suggest, hepatoblastoma tumors have a high degree of heterogeneity that can portend poor prognosis. In this study, we use single-cell transcriptomic techniques to analyze resected human pediatric hepatoblastoma specimens, and identify five hepatoblastoma tumor signatures that may account for the tumor heterogeneity observed in this disease. Notably, patient-derived hepatoblastoma spheroid cultures predict differential responses to treatment based on the transcriptomic signature of each tumor, suggesting a path forward for precision oncology for these tumors. In this work, we define hepatoblastoma tumor heterogeneity with single-cell resolution and demonstrate that patient-derived spheroids can be used to evaluate responses to chemotherapy.
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Affiliation(s)
- Hanbing Song
- Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, 94143, USA
- Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, 94143, USA
- Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Simon Bucher
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA, 94143, USA
- The Liver Center, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Katherine Rosenberg
- The Liver Center, University of California, San Francisco, San Francisco, CA, 94143, USA
- Division of Pediatric Surgery, Department of Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Margaret Tsui
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, 94143, USA
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA, 94143, USA
- The Liver Center, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Deviana Burhan
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA, 94143, USA
- The Liver Center, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Daniel Hoffman
- The Liver Center, University of California, San Francisco, San Francisco, CA, 94143, USA
- Division of Pediatric Surgery, Department of Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Soo-Jin Cho
- Department of Pathology, University of California, San Francisco, San Francisco, CA, 94143, USA
- The Pediatric Liver Center at UCSF Benioff Childrens' Hospitals, San Francisco, CA, 94143, USA
| | - Arun Rangaswami
- The Pediatric Liver Center at UCSF Benioff Childrens' Hospitals, San Francisco, CA, 94143, USA
- Division of Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Marcus Breese
- Division of Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Stanley Leung
- Division of Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - María V Pons Ventura
- Division of Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - E Alejandro Sweet-Cordero
- The Pediatric Liver Center at UCSF Benioff Childrens' Hospitals, San Francisco, CA, 94143, USA
- Division of Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Franklin W Huang
- Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, 94143, USA.
- Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, 94143, USA.
- Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, 94143, USA.
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, 94143, USA.
- Department of Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, CA, 94121, USA.
- Chan Zuckerberg Biohub, San Francisco, CA, 94158, USA.
| | - Amar Nijagal
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, 94143, USA.
- The Liver Center, University of California, San Francisco, San Francisco, CA, 94143, USA.
- Division of Pediatric Surgery, Department of Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA.
- The Pediatric Liver Center at UCSF Benioff Childrens' Hospitals, San Francisco, CA, 94143, USA.
- Eli and Edythe Broad Center of Regeneration Medicine, University of California, San Francisco, San Francisco, CA, 94143, USA.
| | - Bruce Wang
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, 94143, USA.
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA, 94143, USA.
- The Liver Center, University of California, San Francisco, San Francisco, CA, 94143, USA.
- The Pediatric Liver Center at UCSF Benioff Childrens' Hospitals, San Francisco, CA, 94143, USA.
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25
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Sodium thiosulfate for prevention of cisplatin-induced hearing loss: updated survival from ACCL0431. Lancet Oncol 2022; 23:570-572. [DOI: 10.1016/s1470-2045(22)00155-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 02/26/2022] [Accepted: 03/07/2022] [Indexed: 11/21/2022]
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26
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Prognostic implication of serum Alpha-fetoprotein response to neoadjuvant chemotherapy in Hepatoblastoma patients. Int J Health Sci (Qassim) 2022. [DOI: 10.53730/ijhs.v6ns4.6103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Objective: This retrospective study aims to identify the early changes in serum alpha-fetoprotein levels (AFP) and their correlation with the survival outcome of hepatoblastoma patients. Materials and Methods: A total of 68 patients presented to the children's cancer hospital Egypt and the national cancer institute from January 2013 till June 2016 were included in this study. Results: AFP level was measured post-cycle 2 in 60 patients; 44 (73.3%) patients showed a decline in AFP level by >1 log reduction. The 3-year EFS was 75.6% for patients with >1 log reduction in AFP level, compared with 36.5% for those with <1 log reduction (p=0.010). The 3-year OS’ for patients with >1 and <1 log reduction in AFP level were 80.4% and 39.4%, respectively (p=0.005). On multivariate analysis; Patients with AFP log reduction< 1 had worse OS/EFS with hazards ratio (HR): 3.9 and 95% confidence interval (CI):1.4-11.2, p value=0.011 and HR: 3.2 and 95% CI: 1.3-8.9, p value=0.013 respectively. Conclusion: The ease of AFP determination makes it a valuable tool that could be routinely used to evaluate the therapeutic efficacy and predict the survival outcome.
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27
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Woodfield SE, Mistretta BJ, Patel RH, Ibarra AM, Fisher KE, Sarabia SF, Gandhi I, Reuther J, Starosolski Z, Badachhape A, Epps J, Zorman B, Shah AP, Larson SR, Srivastava RK, Shi Y, Espinoza AF, Govindu SR, Whitlock RS, Holloway K, Roy A, Sumazin P, Ghaghada KB, Lopez-Terrada D, Gunaratne PH, Vasudevan SA. HepT1-derived murine models of high-risk hepatoblastoma display vascular invasion, metastasis, and circulating tumor cells. Biol Open 2022; 11:276557. [PMID: 35451474 PMCID: PMC9493725 DOI: 10.1242/bio.058973] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 03/22/2022] [Indexed: 11/20/2022] Open
Abstract
Hepatoblastoma (HB) is the most common pediatric primary liver malignancy, and survival for high-risk disease approaches 50%. Mouse models of HB fail to recapitulate hallmarks of high-risk disease. The aim of this work was to generate murine models that show high-risk features including multifocal tumors, vascular invasion, metastasis, and circulating tumor cells (CTCs). HepT1 cells were injected into the livers or tail veins of mice, and tumor growth was monitored with magnetic resonance and bioluminescent imaging. Blood was analyzed with fluorescence-activated cell sorting to identify CTCs. Intra- and extra-hepatic tumor samples were harvested for immunohistochemistry and RNA and DNA sequencing. Cell lines were grown from tumor samples and profiled with RNA sequencing. With intrahepatic injection of HepT1 cells, 100% of animals grew liver tumors and showed vascular invasion, metastasis, and CTCs. Mutation profiling revealed genetic alterations in seven cancer-related genes, while transcriptomic analyses showed changes in gene expression with cells that invade vessels. Tail vein injection of HepT1 cells resulted in multifocal, metastatic disease. These unique models will facilitate further meaningful studies of high-risk HB. This article has an associated First Person interview with the first author of the paper. Summary: In this work, we developed and thoroughly characterized several unique models of hepatoblastoma derived from the HepT1 cell line that show high-risk features.
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Affiliation(s)
- Sarah E Woodfield
- Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Brandon J Mistretta
- Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA
| | - Roma H Patel
- Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Aryana M Ibarra
- Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Kevin E Fisher
- Department of Pathology and Immunology, Baylor College of Medicine, Texas Children's Hospital Department of Pathology, Houston, TX 77030, USA
| | - Stephen F Sarabia
- Department of Pathology and Immunology, Baylor College of Medicine, Texas Children's Hospital Department of Pathology, Houston, TX 77030, USA
| | - Ilavarasi Gandhi
- Department of Pathology and Immunology, Baylor College of Medicine, Texas Children's Hospital Department of Pathology, Houston, TX 77030, USA
| | - Jacquelyn Reuther
- Department of Pathology and Immunology, Baylor College of Medicine, Texas Children's Hospital Department of Pathology, Houston, TX 77030, USA
| | - Zbigniew Starosolski
- Singleton Department of Radiology, Texas Children's Hospital, Houston, TX 77030, USA
| | - Andrew Badachhape
- Singleton Department of Radiology, Texas Children's Hospital, Houston, TX 77030, USA
| | - Jessica Epps
- Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Barry Zorman
- Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Aayushi P Shah
- Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Samuel R Larson
- Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Rohit K Srivastava
- Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yan Shi
- Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Andres F Espinoza
- Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Saiabhiroop R Govindu
- Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Richard S Whitlock
- Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Kimberly Holloway
- Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA
| | - Angshumoy Roy
- Department of Pathology and Immunology, Baylor College of Medicine, Texas Children's Hospital Department of Pathology, Houston, TX 77030, USA
| | - Pavel Sumazin
- Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ketan B Ghaghada
- Singleton Department of Radiology, Texas Children's Hospital, Houston, TX 77030, USA
| | - Dolores Lopez-Terrada
- Department of Pathology and Immunology, Baylor College of Medicine, Texas Children's Hospital Department of Pathology, Houston, TX 77030, USA
| | - Preethi H Gunaratne
- Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.,Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sanjeev A Vasudevan
- Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
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28
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Zhou S, Malvar J, Chi YY, Stein J, Wang L, Genyk Y, Sposto R, Mascarenhas L. Independent Assessment of the Children's Hepatic Tumors International Collaboration Risk Stratification for Hepatoblastoma and the Association of Tumor Histological Characteristics With Prognosis. JAMA Netw Open 2022; 5:e2148013. [PMID: 35147687 PMCID: PMC8837914 DOI: 10.1001/jamanetworkopen.2021.48013] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 12/17/2021] [Indexed: 11/14/2022] Open
Abstract
IMPORTANCE Hepatoblastoma is the most common pediatric liver malignant neoplasm, and accurate risk stratification is essential for guiding treatment. OBJECTIVE To validate the Children's Hepatic Tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) in an independent cohort of patients with hepatoblastoma and evaluate the association of pretreatment hepatoblastoma histological subtype with prognosis. DESIGN, SETTING, AND PARTICIPANTS This is a single-institution retrospective cohort study of 96 pediatric patients with hepatoblastoma diagnosed and treated between June 1, 2000, and December 31, 2016, with recent therapy and independent of the CHIC-HS discovery cohort. Each patient was assigned a risk group according to CHIC-HS. The histological characteristics of each tumor were assessed based on the International Pediatric Liver Tumor Consensus Classification. Data were analyzed from May 2018 to May 2019. MAIN OUTCOMES AND MEASURES The main outcomes were event-free survival (EFS) and overall survival (OS). Cox regression analysis was used to examine the associations of patient characteristics and tumor histological characteristics with survival. RESULTS A total of 96 patients (median [range] age, 1.9 [0.4-18] years; 36 [38%] girls and 60 [63%] boys) were assessed, including 15 with very low risk, 28 with low risk, 23 with intermediate risk, and 30 with high risk, according to CHIC-HS criteria. There were a total of 13 cancer-related deaths; median (range) follow-up was 3.5 (0.1-17.8) years for those alive at the last follow-up. The estimated 5-year OS rates were 100% in the very low-risk group, 94.7% (95% CI, 68.1%-99.2%) in the low-risk group, 89.2% (95% CI, 63.1%-97.2%) in the intermediate-risk group, and 57.9% (95% CI, 34.6%-75.5%) in the high-risk group. In a multivariable analysis, we confirmed that CHIC-HS significantly estimated EFS (high-risk group vs very low- and low-risk groups: hazard ratio [HR], 45.59; 95% CI, 9.39-209.5; P < .001) and OS (high-risk group vs very low- and low-risk groups: HR, 21.95; 95% CI, 2.76-174.29; P < .001). In the subcohort of 84 patients for whom pretreatment tumor histological data were available, tumor epithelial histological subtypes were found to be significantly associated with both EFS and OS. Patients in the CHIC-HS high-risk group and with embryonal-only histological subtype had the highest risk of relapse or disease progression (high-risk: HR, 42.62; 95% CI, 9.91-203.9; embryonal: HR, 3.28; 95% CI, 1.21-8.9) and death (high-risk: HR, 18.78; 95% CI, 2.31-152.84; embryonal: HR, 7.12; 95% CI, 1.51-33.52). CONCLUSIONS AND RELEVANCE This cohort study found that CHIC-HS performed as expected in an independent cohort that was more recently treated. Incorporation of pretreatment tumor histological data into CHIC-HS may provide additional prognostic value.
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Affiliation(s)
- Shengmei Zhou
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, California
- Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Jemily Malvar
- Cancer and Blood Disease Institute, Division of Hematology and Oncology, Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, California
| | - Yueh-Yun Chi
- Keck School of Medicine, University of Southern California, Los Angeles, California
- Cancer and Blood Disease Institute, Division of Hematology and Oncology, Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, California
| | - James Stein
- Keck School of Medicine, University of Southern California, Los Angeles, California
- Department of Surgery, Children’s Hospital Los Angeles, Los Angeles, California
| | - Larry Wang
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, California
- Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Yuri Genyk
- Keck School of Medicine, University of Southern California, Los Angeles, California
- Department of Surgery, Children’s Hospital Los Angeles, Los Angeles, California
| | - Richard Sposto
- Keck School of Medicine, University of Southern California, Los Angeles, California
- Cancer and Blood Disease Institute, Division of Hematology and Oncology, Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, California
| | - Leo Mascarenhas
- Keck School of Medicine, University of Southern California, Los Angeles, California
- Cancer and Blood Disease Institute, Division of Hematology and Oncology, Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, California
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29
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Fuchs J, Murtha-Lemekhova A, Kessler M, Ruping F, Günther P, Fichtner A, Sturm D, Hoffmann K. A Systematic Review and Meta-Analysis of Malignant Rhabdoid and Small Cell Undifferentiated Liver Tumors: A Rational for a Uniform Classification. Cancers (Basel) 2022; 14:cancers14020272. [PMID: 35053437 PMCID: PMC8774069 DOI: 10.3390/cancers14020272] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/03/2022] [Accepted: 01/04/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Malignant rhabdoid tumors of the liver are very rare pediatric liver tumors with a devastating prognosis. It is currently unclear which histological subtypes of pediatric liver tumors belong to this entity and how these tumors should be treated. In this systematic review with meta-analysis, we analyzed all reports on pediatric patients with malignant rhabdoid liver tumors, but also with so-called small cell undifferentiated liver tumors. This is another rare liver tumor subtype that has recently been regarded to belong to the entity of rhabdoid tumors by some authors. The main result of this study is that these two tumor subtypes show large overlap on several levels and even mixtures of both histological patterns have been documented. Our meta-analysis provides an evidence base for the recommendation to classify these two tumor subtypes as one entity. We showed that treatment of these tumors with hepatoblastoma directed chemotherapy is ineffective and that a therapy with chemotherapy regimens initially applied for soft tissue sarcoma is associated with a significantly better survival. This study represents the highest level of evidence available for these rare liver tumors. Abstract Background: Rhabdoid liver tumors in children are rare and have a devastating prognosis. Reliable diagnosis and targeted treatment approaches are urgently needed. Immunohistochemical and genetic studies suggest that tumors formerly classified as small cell undifferentiated hepatoblastoma (SCUD) belong to the entity of malignant rhabdoid tumors of the liver (MRTL), in contrast to hepatoblastomas with focal small cell histology (F-SCHB). This may have relevant implications on therapeutic approaches. However, studies with larger cohorts investigating the clinical relevance of the histological and genetic similarities for patients are lacking. Purpose: To analyze possible similarities and differences in patient characteristics, tumor biology, response to treatment, and clinical course of patients with MRTL, SCUD and F-SCHB. Applied therapeutic regimens and prognostic factors are investigated. Methods: A systematic literature search of MEDLINE, Web of Science, and CENTRAL was performed for this PRISMA-compliant systematic review. All studies of patients with MRTL, SCUD and F-SCHB that provided individual patient data were included. Demographic, histological, and clinical characteristics of the three subgroups were compared. Overall survival (OS) was estimated with the Kaplan–Meier method and prognostic factors investigated in a multivariable Cox regression model. Protocol registered: PROSPERO 2021 CRD42021258760. Results: Fifty-six studies with a total of 118 patients were included. The two subgroups MRTL and SCUD did not differ significantly in baseline patient characteristics. However, heterogenous diagnostic and therapeutic algorithms were applied. Large histological and clinical overlap between SCUD and MRTL could be shown. Two-year OS was 22% for MRTL and 13% for SCUD, while it was significantly better in F-SCHD (86%). Chemotherapeutic regimens for hepatoblastoma proved to be ineffective for both SCUD and MRTL, but successful in F-SCHB. Soft tissue sarcoma chemotherapy was associated with significantly better survival for MRTL and SCUD, but was rarely applied in SCUD. Patients who did not undergo surgical tumor resection had a significantly higher risk of death. Conclusions: While F-SCHB is a subtype of HB, SCUD should be classified and treated as a type of MRTL. Surgical tumor resection in combination with intensive, multi-agent chemotherapy is the only chance for cure of these tumors. Targeted therapies are highly needed to improve prognosis. Currently, aggressive regimens including soft tissue sarcoma chemotherapy, extensive resection, radiotherapy or even liver transplantation are the only option for affected children.
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Affiliation(s)
- Juri Fuchs
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany; (J.F.); (A.M.-L.)
- Generating Evidence for Diagnosis and Therapy of RarE LIVEr Disease: The RELIVE Initiative for Systematic Reviews and Meta-Analyses, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.K.); (P.G.); (A.F.)
| | - Anastasia Murtha-Lemekhova
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany; (J.F.); (A.M.-L.)
- Generating Evidence for Diagnosis and Therapy of RarE LIVEr Disease: The RELIVE Initiative for Systematic Reviews and Meta-Analyses, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.K.); (P.G.); (A.F.)
| | - Markus Kessler
- Generating Evidence for Diagnosis and Therapy of RarE LIVEr Disease: The RELIVE Initiative for Systematic Reviews and Meta-Analyses, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.K.); (P.G.); (A.F.)
- Department of General, Visceral and Transplantation Surgery, Division of Pediatric Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Fabian Ruping
- Department of General, Visceral and Transplantation Surgery, Division of Pediatric Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Patrick Günther
- Generating Evidence for Diagnosis and Therapy of RarE LIVEr Disease: The RELIVE Initiative for Systematic Reviews and Meta-Analyses, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.K.); (P.G.); (A.F.)
- Department of General, Visceral and Transplantation Surgery, Division of Pediatric Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Alexander Fichtner
- Generating Evidence for Diagnosis and Therapy of RarE LIVEr Disease: The RELIVE Initiative for Systematic Reviews and Meta-Analyses, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.K.); (P.G.); (A.F.)
- Department of Pediatrics I, Division of Pediatric Gastroenterology, University Children’s Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Dominik Sturm
- Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany;
- Hopp Children’s Cancer Center (KiTZ), 69120 Heidelberg, Germany
| | - Katrin Hoffmann
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany; (J.F.); (A.M.-L.)
- Generating Evidence for Diagnosis and Therapy of RarE LIVEr Disease: The RELIVE Initiative for Systematic Reviews and Meta-Analyses, University Hospital Heidelberg, 69120 Heidelberg, Germany; (M.K.); (P.G.); (A.F.)
- Correspondence: ; Tel.: +49-6221-566110; Fax: +49-6221-564215
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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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Wu B, Zhen K, Guo L, Sun C. Diagnostic and Prognostic Value of miRNAs in Hepatoblastoma: A Systematic Review With Meta-Analysis. Technol Cancer Res Treat 2022; 21:15330338221087830. [PMID: 35532186 PMCID: PMC9092586 DOI: 10.1177/15330338221087830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background and aim: Increasing evidence has revealed the valuable diagnostic and prognostic applications of dysregulated microRNAs (miRNAs) in hepatoblastoma (HB), the most common hepatic malignancy during childhood. However, these results are inconsistent and remain to be elucidated. In the present study, we aimed to systematically compile up-to-date information regarding the clinical value of miRNAs in HB. Methods: Articles concerning the diagnostic and prognostic value of single miRNAs for HB were searched from databases. The sensitivity (SEN), specificity (SPE), positive and negative likelihood ratios (PLR and NLR), diagnostic odds ratio (DOR), area under the curve (AUC), and hazard ratios (HRs) were separately pooled to explore the diagnostic and prognostic performance of miRNA. Subgroup and meta-regression analyses were further carried out only in the event of heterogeneity. Results: In all, 20 studies, involving 264 HB patients and 206 healthy individuals, met the inclusion criteria in the 6 included literature articles. For the diagnostic analysis of miRNAs in HB, the pooled SEN and SPE were 0.76 (95% CI: 0.72-0.80) and 0.75 (95% CI: 0.70-0.80), respectively. Moreover, the pooled PLR was 2.79 (95% CI: 2.12-3.66), NLR was 0.34 (95% CI: 0.26-0.45), DOR was 10.24 (95% CI: 6.55-16.00), and AUC was 0.83, indicating that miRNAs had moderate diagnostic value in HB. For the prognostic analysis of miRNAs in HB, the abnormal expressions of miR-21, miR-34a, miR-34b, miR-34c, miR-492, miR-193, miR-222, and miR-224 in patients were confirmed to be associated with a worse prognosis. The pooled HR was 1.74 (95% CI: 1.20-2.29) for overall survival and 1.74 (95% CI: 1.31-2.18) for event-free survival, suggesting its potential as a prognostic indicator for HB. Conclusion: To the best of our knowledge, this is the first comprehensive systematic review and meta-analysis that examines the diagnostic and prognostic role of dysregulated miRNAs in HB patients. The combined meta-analysis results supported the previous individual finds that miRNAs might provide a new, noninvasive method for the diagnostic and prognostic analyses of HB.
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Affiliation(s)
- Bin Wu
- 71532Children's Hospital of Soochow University, Suzhou, China
| | - Kaikai Zhen
- 71532Children's Hospital of Soochow University, Suzhou, China
| | - Lixia Guo
- 71532Children's Hospital of Soochow University, Suzhou, China
| | - Chao Sun
- 71532Children's Hospital of Soochow University, Suzhou, China
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Chen SY, Zamora AK, Lascano D, Zhou S, Kim ES, Stein JE. Outcomes of Central Hepatectomy for Pediatric Liver Tumors. J Surg Res 2021; 268:570-575. [PMID: 34464895 DOI: 10.1016/j.jss.2021.06.077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/08/2021] [Accepted: 06/28/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND Central hepatectomy (CH) is an uncommon surgical technique that is an option for resection of centrally located tumors, with the advantage of sparing normal hepatic parenchyma. Few studies have described outcomes in children undergoing CH. MATERIALS AND METHODS An IRB-approved, retrospective chart review of patients who underwent CH at Children's Hospital Los Angeles between 2005 and 2016 was performed. Data included patient demographics, peri-operative factors, and post-operative outcomes. The IRB approved waiver of consent. RESULTS Eight patients (4F:4M) with median age of 1.9 Y underwent CH: 7 patients for HB and 1 patient for focal nodular hyperplasia. Two of the seven HB patients had metastatic disease at diagnosis. Six of the seven HB patients received a median of 4 rounds (3-7 rounds) of pre-operative chemotherapy. The median operative time was 197.5 Min (143-394 Min) with median blood loss of 175 mL (100-1200 mL). Complications included a bile fluid collection requiring aspiration. Seven patients had negative margins on pathology. One patient with a positive margin successfully completed therapy, without recurrent disease. All patients survived to follow-up, with a median follow-up duration of 1.1 Y (0.1-12.1 Y). Two patients developed recurrent disease requiring formal hepatic lobectomy and orthotopic liver transplantation. These patients had negative pathologic margins, with tumor within 1 mm of resection margins. CONCLUSION CH is an effective alternative to extended hepatectomy for patients with centrally located liver tumors and is associated with good clinical and pathologic outcomes.
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Affiliation(s)
- Stephanie Y Chen
- Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, California.
| | - Abigail K Zamora
- Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, California; Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California.
| | - Danny Lascano
- Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, California.
| | - Shengmei Zhou
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Department of Clinical Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California.
| | - Eugene S Kim
- Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, California; Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California.
| | - James E Stein
- Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, California; Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California.
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Factors influencing recurrence after complete remission in children with hepatoblastoma: A 14-year retrospective study in China. PLoS One 2021; 16:e0259503. [PMID: 34843510 PMCID: PMC8629180 DOI: 10.1371/journal.pone.0259503] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 10/20/2021] [Indexed: 01/01/2023] Open
Abstract
Objective After a complete remission to treatment for hepatoblastoma, some children still have recurrence. We identified and explored the factors that influence recurrence after complete remission in a retrospective study. Methods Of 197 children with hepatoblastoma, 140 (71.1%) achieved initial complete remission and were enrolled in factor analysis. Variables consisted of age, sex, PRE-Treatment EXTent of tumor (PRETEXT) stage, pathologic type, metastatic disease, serum alpha-fetoprotein level, vascular involvement, and surgical margin status. We employed univariate and multivariate analyses to assess the relationship between each factor and tumor recurrence. Results Of 140 children who achieved initial complete remission, 42 (30%) had recurrent hepatoblastoma. The 5-year overall survival rates for the non-recurrence and recurrence group were 99.0% and 78.6%, respectively. The overall 1-year, 3-year, and 5-year recurrence-free survival (RFS) rates were 77.8%, 69.8%, and 69.8%, respectively. All recurrences occurred within 2 years from complete remission. The RFS rate was significantly higher in children younger than 3 years and in those with mixed pathological type, PRETEXT II and III, without metastatic disease, without vascular involvement, and microscopic negative margin than in that of children older than 3 years, with epithelial pathological type, PRETEXT IV, metastatic disease, vascular involvement, and macroscopic positive margin (P < 0.001, = 0.020, < 0.001, = 0.004, = 0.002, and < 0.001, respectively). The independent risk factors for recurrence after complete remission were age ≥3 years, PRETEXT IV, and metastatic disease (P < 0.05). Conclusion Age, PRETEXT stage, metastatic disease, vascular involvement, pathologic type, and surgical margin status might be associated with recurrent hepatoblastoma after complete remission; meanwhile, age ≥3 years, PRETEXT IV, and metastatic disease are independent risk factors of recurrence. Further research is needed on the causes of tumor recurrence, which may improve the long-term outcomes of children with hepatoblastoma.
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Sintusek P, Phewplung T, Sanpavat A, Poovorawan Y. Liver tumors in children with chronic liver diseases. World J Gastrointest Oncol 2021; 13:1680-1695. [PMID: 34853643 PMCID: PMC8603454 DOI: 10.4251/wjgo.v13.i11.1680] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/27/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Liver tumors are rare in children, but the incidence may increase in some circumstances and particularly in chronic liver diseases. Most liver tumors consequent to chronic liver diseases are malignant hepatocellular carcinoma. Other liver tumors include hepatoblastoma, focal nodular hyperplasia, adenoma, pseudotumor, and nodular regenerative hyperplasia. Screening of suspected cases is beneficial. Imaging and surrogate markers of alpha-fetoprotein are used initially as noninvasive tools for surveillance. However, liver biopsy for histopathology evaluation might be necessary for patients with inconclusive findings. Once the malignant liver tumor is detected in children with cirrhosis, liver transplantation is currently considered the preferred option and achieves favorable outcomes. Based on the current evidence, this review focuses on liver tumors with underlying chronic liver disease, their epidemiology, pathogenesis, early recognition, and effective management.
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Affiliation(s)
- Palittiya Sintusek
- Thai Pediatric Gastroenterology, Hepatology and Immunology Research Unit, Department of Pediatrics, Division of Gastroenterology, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok 10330, Thailand
| | - Teerasak Phewplung
- Department of Radiology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Anapat Sanpavat
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Chulalongkorn University, Bangkok 10330, Thailand
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Younes A, Elgendy A, Fadel S, Romeih M, Elwakeel M, Salama A, Azer M, Ahmed G. Surgical Resection of Hepatoblastoma: Factors Affecting Local Recurrence. Eur J Pediatr Surg 2021; 31:432-438. [PMID: 32950033 DOI: 10.1055/s-0040-1717087] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
INTRODUCTION This study aimed to investigate potential factors contributing to local recurrence after surgical resection of hepatoblastoma (HB). MATERIALS AND METHODS This retrospective study involving all patients with HB who underwent nontransplant surgery at our tertiary center between July 2007 and July 2018. Data were analyzed regarding microscopic surgical resection margin, tumor multifocality and extracapsular tumor extension in correlation with local recurrence. These relations were assessed by logistic regression. RESULTS The study included 133 patients with a median age of 1.3 years (range: 0.5-12.8 years). They were classified into 99 cases (74.44%) standard risk and 34 cases (25.56%) high risk. Delayed surgical resection was adopted in all patients. Follow-up to July 2019 revealed that 23 patients (23/133, 17.3%) developed local recurrence, whereas the remaining 110 were locally disease free. Microscopic positive margin (R1) was detected in 29 patients, 8 of them had local recurrence (p = 0.097). Regarding tumor multifocality, there were 12 patients who had multifocal lesions, 3 of them developed local recurrence (p = 0.459). Forty-four patients had extracapsular tumor extension in their pathological reports, 12 of them had local recurrence (p = 0.032). CONCLUSION Extracapsular tumor extension was a significant prognostic factor of local recurrence after surgical resection of HB. R1 margin does not necessarily require a second resection, and it could achieve accepted results when combined with adjuvant platinum-based chemotherapy. However, patients who are not eligible for surgical resection must be transferred for primary transplantation to obtain favorable outcome.
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Affiliation(s)
- Alaa Younes
- Department of Surgical Oncology, Children's Cancer Hospital, Cairo, Egypt
| | - Ahmed Elgendy
- Surgical Oncology Unit, Department of Surgery, Tanta University, Tanta, Egypt
| | - Sayed Fadel
- Department of Pediatric Oncology, National Cancer Institute-Cairo University, Cairo, Egypt.,Department of Pediatric Oncology, Children's Cancer Hospital, Cairo, Egypt
| | - Marwa Romeih
- Department of Radiology, Helwan University, Cairo, Egypt.,Department of Radiology, Children's Cancer Hospital, Cairo, Egypt
| | - Madeeha Elwakeel
- Department of Radiology, Children's Cancer Hospital, Cairo, Egypt
| | - Asmaa Salama
- Department of Pathology, National Cancer Institute-Cairo University, Cairo, Egypt.,Department of Pathology, Children's Cancer Hospital, Cairo, Egypt
| | - Magda Azer
- Department of Anesthesia, National Cancer Institute, Cairo University, Cairo, Egypt.,Department of Anesthesia, Children's Cancer Hospital, Cairo, Egypt
| | - Gehad Ahmed
- Department of Surgery, Helwan University, Cairo, Egypt
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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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Jiang Y, Sun J, Xia Y, Cheng Y, Xie L, Guo X, Guo Y. Preoperative Assessment for Event-Free Survival With Hepatoblastoma in Pediatric Patients by Developing a CT-Based Radiomics Model. Front Oncol 2021; 11:644994. [PMID: 33937051 PMCID: PMC8086552 DOI: 10.3389/fonc.2021.644994] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 02/11/2021] [Indexed: 12/12/2022] Open
Abstract
Objective: To explore a CT-based radiomics model for preoperative prediction of event-free survival (EFS) in patients with hepatoblastoma and to compare its performance with that of a clinicopathologic model. Patients and Methods: Eighty-eight patients with histologically confirmed hepatoblastoma (mean age: 2.28 ± 2.72 years) were recruited from two institutions between 2002 and 2019 for this retrospective study. They were divided into a training cohort (65 patients from institution A) and a validation cohort (23 patients from institution B). Radiomics features were extracted manually from pretreatment CT images in the portal venous (PV) phase. The least absolute shrinkage and selection operator (LASSO) Cox regression model was applied to construct a “radiomics signature” and radiomics score (Rad-score) for EFS prediction. Then, a nomogram incorporating the Rad-score, updated staging system, and significant variables of clinicopathologic risk (age, alpha-fetoprotein (AFP) level, histology subtype, tumor diameter) as the radiomic model, clinicopathologic model, and combined clinicopathologic-radiomic model were built for EFS estimation in the training cohort, the performance of which was assessed in an external-validation cohort with respect to clinical usefulness, discrimination, and calibration. Results: Nine survival-relevant features were selected for a radiomics signature and Rad-score building. Multivariable analysis revealed that histology subtype (P = 0.01), PV (P = 0.001) invasion, and metastasis (P = 0.047) were independent risk factors of EFS. Patients were divided into low- and high-risk groups based on the Rad-score with a cutoff of 0.08 according to survival outcome. The radiomics signature-incorporated nomogram showed good performance (P < 0.001) for EFS estimation (C-Index: 0.810; 95% CI: 0.738–0.882), which was comparable with that of the clinicopathological model for EFS estimation (C-Index: 0.81 vs. 0.85). The radiomics-based nomogram failed to show incremental prognostic value compared with that using the clinicopathologic model. The combined model (radiomics signature plus clinicopathologic parameters) showed significant improvement in the discriminatory accuracy, along with good calibration and greater net clinical benefit, of EFS (C-Index: 0.88; 95% CI: 0.829–0.933). Conclusion: The radiomics signature can be used as a prognostic indicator for EFS in patients with hepatoblastoma. A combination of the radiomics signature and clinicopathologic risk factors showed better performance in terms of EFS prediction in patients with hepatoblastoma, which enabled precise clinical decision-making.
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Affiliation(s)
- Yi Jiang
- West China Second University Hospital, Sichuan University, Chengdu, China
| | - Jingjing Sun
- West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yuwei Xia
- Huiying Medical Technology, Beijing, China
| | - Yan Cheng
- West China Second University Hospital, Sichuan University, Chengdu, China
| | - Linjun Xie
- West China Second University Hospital, Sichuan University, Chengdu, China
| | - Xia Guo
- West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yingkun Guo
- West China Second University Hospital, Sichuan University, Chengdu, China
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Abstract
The most recent advance in the care of children diagnosed with hepatoblastoma and hepatocellular carcinoma is the Pediatric Hepatic International Tumor Trial, which opened to international enrollment in 2018. It is being conducted as a collaborative effort by the pediatric multicenter trial groups in North America, Europe, and the Far East. This international effort was catalyzed by a new unified global risk stratification system for hepatoblastoma, an international histopathologic consensus classification for pediatric liver tumors, and a revised 2017 collaborative update of the PRE-Treatment EXTent of disease radiographic based staging system.
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Affiliation(s)
- Rebecka Meyers
- Division Pediatric Surgery, University of Utah, Primary Children's Hospital, 100 North Mario Capecchi Drive, Suite 3800, Salt Lake City, UT 84113, USA.
| | - Eiso Hiyama
- Department of Pediatric Surgery, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-Ku, Hiroshima 734-8551, Japan
| | - Piotr Czauderna
- Department of Surgery and Urology for Children and Adolescents, Medical University of Gdansk, Marii Skłodowskiej-Curie 3a, 80-210 Gdańsk, Poland
| | - Greg M Tiao
- Division Pediatric Surgery, Cincinnati Children's Hospital and Medical Center, 3333 Burnet Ave, Cincinnati, Ohio 45229, USA
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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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Neonatal Liver Tumors. Clin Perinatol 2021; 48:83-99. [PMID: 33583509 DOI: 10.1016/j.clp.2020.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma. Sci Rep 2021; 11:2967. [PMID: 33536467 PMCID: PMC7859402 DOI: 10.1038/s41598-021-82542-4] [Citation(s) in RCA: 157] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 01/06/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatoblastoma (HB) is the most common pediatric liver malignancy. High-risk patients have poor survival, and current chemotherapies are associated with significant toxicities. Targeted therapies are needed to improve outcomes and patient quality of life. Most HB cases are TP53 wild-type; therefore, we hypothesized that targeting the p53 regulator Murine double minute 4 (MDM4) to reactivate p53 signaling may show efficacy. MDM4 expression was elevated in HB patient samples, and increased expression was strongly correlated with decreased expression of p53 target genes. Treatment with NSC207895 (XI-006), which inhibits MDM4 expression, or ATSP-7041, a stapled peptide dual inhibitor of MDM2 and MDM4, showed significant cytotoxic and antiproliferative effects in HB cells. Similar phenotypes were seen with short hairpin RNA (shRNA)-mediated inhibition of MDM4. Both NSC207895 and ATSP-7041 caused significant upregulation of p53 targets in HB cells. Knocking-down TP53 with shRNA or overexpressing MDM4 led to resistance to NSC207895-mediated cytotoxicity, suggesting that this phenotype is dependent on the MDM4-p53 axis. MDM4 inhibition also showed efficacy in a murine model of HB with significantly decreased tumor weight and increased apoptosis observed in the treatment group. This study demonstrates that inhibition of MDM4 is efficacious in HB by upregulating p53 tumor suppressor signaling.
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Huang J, Hu Y, Jiang H, Xu Y, Lu S, Sun F, Zhu J, Wang J, Sun X, Liu J, Zhen Z, Zhang Y. CHIC Risk Stratification System for Predicting the Survival of Children With Hepatoblastoma: Data From Children With Hepatoblastoma in China. Front Oncol 2020; 10:552079. [PMID: 33312943 PMCID: PMC7708347 DOI: 10.3389/fonc.2020.552079] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 10/22/2020] [Indexed: 12/04/2022] Open
Abstract
Objective The aim of this study was to compare the accuracy of the Children’s Oncology Group (COG) risk stratification system to the Children’s Hepatic tumor International Collaboration (CHIC) risk stratification system for predicting the prognosis of Chinese children with hepatoblastoma (HB). Methods Clinicopathological data of 86 patients diagnosed with HB between January 2014 and December 2017 were retrieved. The study endpoints were the 1- and 3-year overall survival (OS) and disease-free survival (DFS) were analyzed to evaluate the predictive value. Results The 1-, 3-year OS and DFS of the 86 patients were 86.0%, 76.3%, and 74.4%, 54.0%, respectively. Univariate analyses revealed that age at diagnosis had a significant role in prognosis for both OS and DFS, along with PRETEXT staging and metastasis at diagnosis. Multivariate analysis showed that metastasis at diagnosis (HR 3.628, 95% CI 1.404-9.378, P=0.008), PRETEXT staging system (HR 2.176, 95% CI 1.230-3.849, P=0.008) and age at diagnosis (HR 2.268, 95% CI 1.033-4.982, P=0.041) were independent factors for OS. For DFS, the independent factors were the PRETEXT staging system (HR 2.241, 95% CI 1.533-3.277, P<0.001) and age at diagnosis (HR 1.792, 95% CI 1.018-3.154, P=0.043). Both COG and CHIC risk stratification systems could effectively predict the prognosis of children with HB for OS. For DFS, the CHIC risk stratification system was more effective. In addition, the CHIC risk stratification system had a higher c-index (OS 0.743, DFS 0.730), compared to the COG risk stratification system (OS 0.726, DFS 0.594). Conclusion Age at diagnosis played a significant role in prognosis. Compared to the COG risk stratification system, the CHIC risk stratification system was superior in predicting the survival of Chinese children with HB.
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Affiliation(s)
- Junting Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yang Hu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hong Jiang
- Department of Pediatric Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanjie Xu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Suying Lu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Feifei Sun
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jia Zhu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Juan Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiaofei Sun
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Juncheng Liu
- Department of Pediatric Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zijun Zhen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yizhuo Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
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Vishnoi JR, Sasidhar A, Misra S, Pareek P, Khera S, Kumar S, Jain A. Hepatoblastoma in a Young Adult: a Rare Case Report and Review of the Literature. J Gastrointest Cancer 2020; 51:319-324. [PMID: 31140065 DOI: 10.1007/s12029-019-00256-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Jeewan Ram Vishnoi
- Department of Surgical Oncology, All India Institute of Medical Sciences, Basni Industrial Area, Phase II, Jodhpur, India.
| | - Ajai Sasidhar
- Department of Surgical Oncology, All India Institute of Medical Sciences, Basni Industrial Area, Phase II, Jodhpur, India
| | - Sanjeev Misra
- Department of Surgical Oncology, All India Institute of Medical Sciences, Basni Industrial Area, Phase II, Jodhpur, India
| | - Puneet Pareek
- Department of Radiotherapy, All India Institute of Medical Sciences, Jodhpur, India
| | - Sudeep Khera
- Department of Pathology, All India Institute of Medical Sciences, Jodhpur, India
| | - Sushil Kumar
- Department of Surgical Oncology, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, India
| | - Ankit Jain
- Department of Surgical Oncology, All India Institute of Medical Sciences, Basni Industrial Area, Phase II, Jodhpur, India
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MacDonell-Yilmaz R, Anderson K, DeNardo B, Sprinz P, Padula WV. Cost-effectiveness Analysis of Screening Extremely Low Birth Weight Children for Hepatoblastoma Using Serum Alpha-fetoprotein. J Pediatr 2020; 225:80-89.e4. [PMID: 32470475 PMCID: PMC8855955 DOI: 10.1016/j.jpeds.2020.05.041] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 05/04/2020] [Accepted: 05/20/2020] [Indexed: 01/03/2023]
Abstract
OBJECTIVES To evaluate the cost-effectiveness of screening children born at extremely low birth weight (ELBW) for hepatoblastoma using serial serum alpha-fetoprotein measurements. STUDY DESIGN We created a decision tree to evaluate the cost effectiveness of screening children born at ELBW between 3 and 48 months of age compared with current standard of care (no screening). Our model used discounted lifetime costs and monetary benefits in 2018 US dollars, based on estimates in the published literature. The effects of uncertainty in model parameters were also assessed using univariate sensitivity analyses, in which we changed the values for one parameter at a time to assess the effect on the estimated incremental cost-effectiveness ratio. RESULTS For the estimated 55 699 children born at ELBW in the US each year, this screening is associated with 77.7 additional quality-adjusted life-years (QALYs) at a cost of $8.7 million. This results in an incremental cost-effectiveness ratio of about $112 000/QALY, which is considered cost effective from a US societal perspective. For children diagnosed with hepatoblastoma, our model finds that the screening regimen is associated with a 10.1% increase in survival, a 4.18% increase in expected QALYs, and a $245 184 decrease in expected cost. CONCLUSIONS Screening ELBW children for hepatoblastoma between 3 and 48 months of age dominates the alternative and is cost effective from a societal perspective.
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Affiliation(s)
| | - Kelly Anderson
- Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | | | | | - William V. Padula
- Department of Pharmaceutical & Health Economics, School of Pharmacy,Leonard D. Schaeffer Center for Health Policy & Economics, University of Southern California, Los Angeles, CA
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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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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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Shaughnessy MP, Spencer-Manzon M, Cowles RA. Antenatally detected liver and biliary pathology. Semin Pediatr Surg 2020; 29:150939. [PMID: 32861443 DOI: 10.1016/j.sempedsurg.2020.150939] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Liver and biliary pathology in the neonate are rare and include a broad range of structural, neoplastic, infectious, genetic, and metabolic diseases. While most conditions present postnatally, antenatal detection is increasing given recent advances in antenatal imaging capabilities. In certain structural or obstructive liver diseases, antenatal detection now proves essential to help guide treatment and prevent morbidity. We review the epidemiology, pathophysiology, common antenatal diagnostic findings, and recommendations for surgical liver and biliary pathology in the neonate.
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Affiliation(s)
- Matthew P Shaughnessy
- Department of Surgery, Division of Pediatric Surgery, Yale University School of Medicine, 333 Cedar St., FMB 131, New Haven, CT 06510, USA
| | | | - Robert A Cowles
- Department of Surgery, Division of Pediatric Surgery, Yale University School of Medicine, 333 Cedar St., FMB 131, New Haven, CT 06510, USA.
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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: 19] [Impact Index Per Article: 3.8] [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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Surgical Therapy for Pediatric Hepatoblastoma in the USA over the Last Decade: Analysis of the National Cancer Database. J Gastrointest Cancer 2020; 52:547-556. [PMID: 32458263 DOI: 10.1007/s12029-020-00421-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
INTRODUCTION Hepatoblastoma (HB) is a rare childhood malignancy with hepatic resection (HR) or liver transplantation (LT) providing the best chance of cure. In this study, we analyze the National Cancer Database lacks (NCDB) to compare outcomes following HR and LT for HB. METHODS Review of the US experience with surgical (HR and LT) management of pediatric (< 18 years) HB over the last decade (2004-2014) using data extracted from the NCDB. RESULTS A total of 628 children underwent surgical treatment for HB during the study period: HR in 525 (83.6%) and LT in 103 (16.4%). The two groups were comparable for age, sex, race, tumor size, and metastatic disease at initial diagnosis. LT group had significantly higher number of patients with bilobar disease (40 vs 21%; p < 0.001), longer median time from diagnosis to surgery (120 vs 78 days; p < 0.001), and longer post-operative length of stay (LOS) (14 vs 6 days; p < 0.001). There were no differences in rates of 30-day readmission and 30- or 90-day mortality between groups. Both groups had comparable 5-year overall survival (OS) (84.1% HR vs 80.0% LT; p = 0.4). Univariate analysis identified metastatic disease at initial presentation (HR 2.56, CI 1.51-4.35) and age ≥ 4 years (HR 2.68, CI 1.5-4.7) as risk factors for worse overall 5-yr OS, while administration of adjuvant chemotherapy was associated with improved 5-yr OS (92.3% with chemo vs 85.4% without chemo; HR 0.51, CI 0.31-0.84). CONCLUSION The outcome of HB has improved compared with historical controls. Age at presentation, metastatic disease, and post-operative chemotherapy impact outcomes.
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50
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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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