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Treatment intensification has improved survival in patients with hepatoblastoma (HB); however, these treatments are associated with an increased risk of late effects, including second malignant neoplasms (SMNs). Data is limited regarding SMNs following HB treatment. Cases of SMNs following treatment for HB reported in the literature and from personal communication were analyzed to further assess this late effect. Thirty-eight patients were identified. The median age at diagnosis of HB was 16 months (range: 3 to 168 mo). All patients had received a platinum agent, and almost all had anthracycline exposure. The SMNs reported were hematopoietic malignancies (n=19), solid tumors (n=12), and post-transplant lymphoproliferative disorder (n=7). Of the 36 patients with outcome data, 19 survived. SMNs following HB treatment were primarily seen in patients with chemotherapy exposure, a history of liver transplantation, hereditary tumor predisposition syndromes, and/or a history of radiation treatment. Hematopoietic malignancies were the most common SMN reported in this cohort and were diagnosed earlier than other SMNs. Prospective collection of data through a companion late effects study or international registry could be used to further evaluate the rates and risks of SMNs as well as tumor predisposition syndromes in patients treated for HB.
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Neoplasias Hematológicas , Hepatoblastoma , Neoplasias Hepáticas , Neoplasias Primarias Secundarias , Humanos , Hepatoblastoma/epidemiología , Hepatoblastoma/terapia , Hepatoblastoma/complicaciones , Estudios Prospectivos , Factores de Riesgo , Incidencia , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Hematológicas/complicaciones , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/complicacionesRESUMEN
Introduction: The place of laparoscopy in the resection of Wilms' tumors has remained debatable, but evidence that neoadjuvant chemotherapy causes tumor shrinkage has made laparoscopic nephrectomy (LN) a feasible option. Laparoscopic nephron-sparing surgery (NSS) is technically very demanding and seems to be feasible and effective only when performed by a very experienced surgeon. Aim: We report 7 cases of laparoscopic nephrectomy and 1 case of laparoscopic heminephrectomy for Wilms' tumor. Material and methods: Forty-two consecutive children with primary renal tumor underwent nephrectomy between 2013 and 2020; 11 had an LN. Among them there were 8 children with Wilms' tumor, with age between 13 months and 7 years. All patients received neoadjuvant chemotherapy according to the current SIOP protocol. The mean tumor volume before and after chemotherapy was 174.4 ml (range: 14.7-501) and 32.8 ml (range: 4.3-68) respectively. Results: Seven laparoscopic nephrectomies and one heminephrectomy were performed. No patient had an intraoperative tumor rupture. All children had an attempt of lymph node sampling (their number per pathology assessment was in the range 0-5). There were no intraoperative events. One complication after heminephrectomy occurred, which was urine leak. Five patients had stage I tumor and 3 had stage II. Seven patients had an intermediate-risk and one had a high-risk tumor. There were no local or distant relapses. All patients remained disease-free at a median follow-up of 71 months (range: 16-94). Conclusions: This report demonstrates the feasibility of LN in children with Wilms' tumors. The patients should be carefully selected and specific training in laparoscopy is necessary, particularly with regard to laparoscopic heminephrectomy.
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BACKGROUND AND AIMS: Hepatoblastoma (HB) is the predominant form of pediatric liver cancer, though it remains exceptionally rare. While treatment outcomes for children with HB have improved, patients with advanced tumors face limited therapeutic choices. Additionally, survivors often suffer from long-term adverse effects due to treatment, including ototoxicity, cardiotoxicity, delayed growth, and secondary tumors. Consequently, there is a pressing need to identify new and effective therapeutic strategies for patients with HB. Computational methods to predict drug sensitivity from a tumor's transcriptome have been successfully applied for some common adult malignancies, but specific efforts in pediatric cancers are lacking because of the paucity of data. APPROACH AND RESULTS: In this study, we used DrugSense to assess drug efficacy in patients with HB, particularly those with the aggressive C2 subtype associated with poor clinical outcomes. Our method relied on publicly available collections of pan-cancer transcriptional profiles and drug responses across 36 tumor types and 495 compounds. The drugs predicted to be most effective were experimentally validated using patient-derived xenograft models of HB grown in vitro and in vivo. We thus identified 2 cyclin-dependent kinase 9 inhibitors, alvocidib and dinaciclib as potent HB growth inhibitors for the high-risk C2 molecular subtype. We also found that in a cohort of 46 patients with HB, high cyclin-dependent kinase 9 tumor expression was significantly associated with poor prognosis. CONCLUSIONS: Our work proves the usefulness of computational methods trained on pan-cancer data sets to reposition drugs in rare pediatric cancers such as HB, and to help clinicians in choosing the best treatment options for their patients.
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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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Management of hepatoblastoma (HB), the most frequent pediatric liver cancer, is based on surgical resection and perioperative chemotherapy regimens. In this study, we aimed to identify actionable targets in HB and assess the efficacy of molecular therapies in preclinical models of HB. Paired tumor and adjacent tissues from 31 HBs and a validation set of 50 HBs were analyzed using RNA-seq, SNP, and methylation arrays. IGF2 overexpression was identified as the top targetable HB driver, present in 71% of HBs (22/31). IGF2high tumors displayed progenitor cell features and shorter recurrence-free survival. IGF2 overexpression was associated in 91% of cases with fetal promoter hypomethylation, ICR1 deregulation, 11p15.5 loss of heterozygosity or miR483-5p overexpression. The antitumor effect of xentuzumab (a monoclonal antibody targeting IGF1/2) alone or in combination with the conventional therapeutic agent cisplatin was assessed in HB cell lines, in PDX-derived HB organoids and in a xenograft HB murine model. The combination of xentuzumab with cisplatin showed strong synergistic antitumor effects in organoids and in IGF2high cell lines. In mice (n = 55), the combination induced a significant decrease in tumor volume and improved survival compared with cisplatin alone. These results suggest that IGF2 is an HB actionable driver and that, in preclinical models of HB, the combination of IGF1/2 inhibition with cisplatin induces superior antitumor effects than cisplatin monotherapy. Overall, our study provides a rationale for testing IGF2 inhibitors in combination with cisplatin in HB patients with IGF2 overexpression.
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Hepatoblastoma , Neoplasias Hepáticas , Humanos , Animales , Ratones , Hepatoblastoma/tratamiento farmacológico , Hepatoblastoma/genética , Hepatoblastoma/patología , Cisplatino/farmacología , Cisplatino/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Metilación de ADN , Genómica , Factor II del Crecimiento Similar a la Insulina/genéticaRESUMEN
Small cell undifferentiated (SCU) histology and alpha-fetoprotein (AFP) levels below 100 ng/mL have been reported as poor prognostic factors in hepatoblastoma (HB); subsequent studies reported SMARCB1 mutations in some SCU HBs confirming the diagnosis of rhabdoid tumor. The Children's Hepatic tumors International Collaboration (CHIC) database was queried for patients with HB who had AFP levels less than 100 ng/mL at diagnosis or were historically diagnosed as SCU HBs. Seventy-three of 1605 patients in the CHIC database were originally identified as SCU HB, HB with SCU component, or HB with low AFP levels. Upon retrospective review, they were re-classified as rhabdoid tumors (n = 11), HB with SCU component (n = 41), and HB with low AFP (n = 14). Seven were excluded for erroneously low AFP levels. Overall survival was 0% for patients with rhabdoid tumors, 76% for patients with HB with SCU component, and 64% for patients with HB with AFP less than 100 ng/mL. Patients with HB with SCU component or low AFP should be assessed for SMARCB1 mutations and, if confirmed, treated as rhabdoid tumors. When rhabdoid tumors are excluded, the presence of SCU component and low AFP at diagnosis were not associated with poor prognosis in patients diagnosed with HB.
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Hepatoblastoma is the most common primary malignant paediatric liver tumour and surgery remains the cornerstone of its management. The aim of this article is to present the principles of surgical treatment of hepatoblastoma. All aspects of surgery in hepatoblastoma are discussed, from biopsy, through conventional and laparoscopic liver resections, to extreme resection with adjacent structures, staged hepatectomy and transplantation.
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Hepatoblastoma , Neoplasias Hepáticas , Trasplante de Hígado , Niño , Humanos , Lactante , Hepatoblastoma/cirugía , Hepatoblastoma/patología , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patología , Hepatectomía , Biopsia , Resultado del TratamientoAsunto(s)
Refugiados , Trastornos por Estrés Postraumático , Humanos , Niño , Etnicidad , Terapia de Reemplazo RenalRESUMEN
Purpose: To present a single-centre experience in bi- and uni-segmentectomies for primary liver tumours in children. METHODS: This study included 23 patients that underwent (bi)segmentectomy. There were 15 malignant tumours (hepatoblastoma-13 patients), 7 benign tumours, and 1 calcifying nested stromal epithelial tumour. RESULTS: The median tumour diameter was 52 mm (range 15-170 mm). Bisegmentectomy 2-3 was most frequently performed (seven patients), followed by bisegmentectomy 5-6 (four patients). The median operative time was 225 min (range 95-643 min). Intraoperative complications occurred in two patients-small bowel perforation in one and an injury of the small peripheral bile duct resulting in biloma in the other. The median resection margin in patients with hepatoblastoma was 3 mm (range 1-15 mm). Microscopically negative margin status was achieved in 12 out of 13 patients. There were two recurrences. After a median follow-up time of 38 months (range 12-144 months), all 13 patients with HB were alive with no evidence of disease. Two relapsed patients were alive with no evidence of disease. CONCLUSIONS: From the available literature and data presented here, we propose that (bi)segmentectomy can become a viable surgical option in carefully selected paediatric patients and is sufficient to achieve a cure. Further studies evaluating the impact of parenchymal preservation surgery on surgical and oncological outcome should be conducted with a larger dataset.
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COVID-19 , Niño , Humanos , COVID-19/epidemiología , Pandemias , SARS-CoV-2 , Encuestas y Cuestionarios , Europa (Continente)/epidemiologíaRESUMEN
According to a recent national audit, the cost of treating patients in geriatric wards is 20-30% less compared to those treated in internal medicine wards. Yet, geriatric care remains largely underdeveloped in Poland, with few human, material, and financial resources. Despite numerous attempts to raise the profile of geriatrics over the years, little progress has been achieved. In 2019, experts under the President of Poland proposed the creation of a network of Health Centres 75+ as the first pillar of geriatric care. These are meant to provide ambulatory services for older people and coordinate provision of other health and social care services at the county level. The goal is to create a community model of care, whereby older people would receive needed services close to their place of residence, allowing them to live independently for as long as possible. Although the proposal has been welcomed by the geriatric community and the patients, the acute shortages of human, physical, and financial resources raise concerns about its feasibility. However, the new strategic plans for the health system propose solutions that appear to be supportive of the new proposal, and the Office of the President is discussing joining forces with the Ministry of Health to improve its chances of implementation. Given the increasing pace of population ageing and underdeveloped provision of geriatric services, these efforts are very much needed.
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Geriatría , Anciano , Envejecimiento , Instituciones de Atención Ambulatoria , Humanos , PoloniaRESUMEN
Introduction: Peritoneal metastases occur in cancers that spread to the peritoneal cavity and indicate the advanced stage of the disease. In children they are mainly seen in sarcomas, Gastrointestinal Stromal Tumors and primary disseminated ovarian tumors. Inflammatory Myofibroblastic Tumor (IMT) is a very rare lesion, characterized by an unpredictable clinical course. The absorption of chemotherapeutic agents through the peritoneal-plasma barrier (PPB) is minimized, thus HIPEC procedure limits the systemic exposure to chemotherapy and permits the administration of its higher doses. The main purpose of HIPEC is to remove the visible macroscopic disease in order to achieve complete cytoreduction (CRS). HIPEC Procedure in Children: Several papers deal with the CRS and HIPEC in children and adolescents, however pediatric experience is still limited. Thus far, the HIPEC procedure has been carried out on patients over 2 years old. The most common indication for the surgery and the best outcome was experienced by patients with desmoplastic small round cell tumor (DSRCT). Most patients received intraperitoneal cisplatin. HIPEC Modification: A 5-month-old infant was admitted to the Department of Pediatric Oncology due to the abdominal distention and blood in the stool. The Computed Tomography (CT) revealed a solid-cystic mass in the right abdominal area. The primary tumor and numerous peritoneal metastasis were removed and the Inflammatory Myofibroblastic Tumor (IMT) was diagnosed. The patient underwent subsequently CRS and modified HIPEC procedure. To avoid overheating of the infant, the intraperitoneal normothermic chemoperfusion was performed. Due to the low body weight a modified dosage of intraperitoneal doxorubicin was used. The child underwent standard postoperative chemotherapy and received crizotinib therapy. At 12 months follow-up since treatment completion the patient remains in complete remission. To our knowledge this is the youngest patient, the only infant and the first pediatric patient with IMT who underwent the modified HIPEC procedure in the world. Conclusions: CRS and HIPEC is technically possible also in infants. For its safe course patients selection and technique modification are necessary. Use of HIPEC should be also considered in intraperitoneally disseminated IMT. A complete cytoreductive surgery as the first HIPEC step seems to be the key factor in survival.
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BACKGROUND/PURPOSE: Neuroblastic tumors are the most common pediatric extracranial solid tumors in infants and very young children. Although, especially in newborns, there is an increasing number of situations in which observation alone is used, surgery remains an important step in the treatment of neuroblastoma but can be complicated by arterial vasospasm in the surgical field. The aim of this two-center retrospective study was to analyze the occurrence of arterial constriction as a complication of neuroblastic tumors resection. METHODS: Medical records of patients who were treated surgically for neuroblastic tumors in the years 2012-2019 were reviewed. RESULTS: For 8 years, 113 children were treated for neuroblastic tumors. The treatment included both primary and delayed surgery after initial chemotherapy carried out according to SIOPEN protocols. In 11 out of 113 cases (9.7%) local arterial constriction was observed. In 6 out of 11 cases an attempt was made to save the organ, however, two patients suffered from kidney atrophy, two other partial kidney infarctions, one child suffered from partial limb paresis, and another from brain ischemia and death. CONCLUSIONS: Local arterial constriction constitutes a relatively common (10% of cases) and severe complication of neuroblastic tumors resection. Efficacy of local application of papaverine based on our experience remains unproven hence further research is warranted.
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Neuroblastoma , Niño , Preescolar , Constricción , Humanos , Lactante , Recién Nacido , Infarto , Neuroblastoma/cirugía , Estudios RetrospectivosRESUMEN
Gastrointestinal stromal tumors and neuroendocrine tumors in adult and pediatric populations differ immensely. Despite these established differences, the extreme rarity of gastrointestinal stromal tumors and neuroendocrine tumors in the pediatric population has resulted in the lack of consensus management guidelines, making optimal surgical approaches unclear. Comprehensive management principles to guide surgical approaches in adult literature are extensive. However, these are still lacking for pediatric patients. International cooperation to develop standardized pediatric-specific guidelines is urgently warranted in the future. This article highlights the vast differences between adult and pediatric parameters and provides recommendations on optimal and novel surgical approaches in children.
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Tumores del Estroma Gastrointestinal , Tumores Neuroendocrinos , Adulto , Niño , Consenso , Tumores del Estroma Gastrointestinal/cirugía , Humanos , Tumores Neuroendocrinos/cirugíaRESUMEN
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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Carcinoma Hepatocelular , Hepatoblastoma , Neoplasias Hepáticas , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/terapia , Niño , Hepatoblastoma/epidemiología , Hepatoblastoma/terapia , Humanos , Neoplasias Hepáticas/terapia , Estudios Multicéntricos como AsuntoRESUMEN
BACKGROUND: Laparoscopy for the resection of liver tumors in children has remained undeveloped in comparison to adults. Most of the indications for pediatric laparoscopic hepatic surgery have been limited to diagnostic laparoscopy (biopsy). Over the past ten years, however, laparoscopic liver resections for pediatric hepatic diseases have been performed successfully, and many case reports have been published. METHODS: The authors report 6 cases of laparoscopic hepatic resection of benign tumors in children. The most important aspects of surgical technique are presented. There were 3 boys and 3 girls, with age between 4â¯months and 16â¯years. The lesions were located in the following segments: II and III (4 patients), I (1), V (1). The maximum tumor size was 7â¯cm. RESULTS: One anatomical (left bisegmentectomy) and 5 nonanatomical resections were performed. Conversion to laparotomy was necessary in 1 patient owing to bleeding from the posterior branch of the right hepatic artery. There were no postoperative complications and patients were discharged on postoperative day 4, 5, 5, 5, 7 and 3 accordingly. The postoperative pathology of the specimens confirmed their benign nature: infantile hemangioendothelioma (1), nested stromal epithelial tumor (1), focal nodular hyperplasia (3), mixed benign tumor (hamartoma + vascular malformation) (1). CONCLUSIONS: This report demonstrates the feasibility of a laparoscopic hepatic resection in children. On the other hand, laparoscopic liver resection is challenging and teamwork and specific training are necessary.
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Laparoscopía , Hepatopatías , Neoplasias Hepáticas , Adulto , Niño , Femenino , Hepatectomía , Humanos , Lactante , Laparotomía , Hepatopatías/cirugía , Neoplasias Hepáticas/cirugía , MasculinoRESUMEN
The European Union of Medical Specialists (UEMS) Section and Board of Pediatric surgery was founded more than 40 years ago. Since then major activities have been related to the improvement of quality of care of pediatric surgery in Europe. Remarkable success was achieved in the development of pediatric surgery as an independent specialty all over Europe. Other major successful activities of the UEMS Section and Board of Pediatric Surgery consisted of the development of a high-quality European examination and delineating a minimal common standard in pediatric surgery training in the form of European training requirements. Recommendations drawn from examination experience support that candidates who achieve weaker passes in part 1 may wish to consider more practice before attempting part 2 due to the weak correlation between the two scores. It may be helpful for candidates to consider having some experience working in an English-speaking clinical setting, if not truly fluent in English, to improve their chances of being successful in the part 2 examination. Other achievements of the Section were accreditation of the training centers in Europe and European Census in pediatric surgery project. All the aforementioned activities led to standardization and harmonization of pediatric surgery, as well as contributed to increasing quality of pediatric surgical service throughout Europe.
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Pediatría/organización & administración , Sociedades Médicas/historia , Especialidades Quirúrgicas/organización & administración , Europa (Continente) , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Pediatría/educación , Sociedades Médicas/organización & administración , Especialidades Quirúrgicas/educaciónRESUMEN
BACKGROUND: Undifferentiated embryonal sarcomas of the liver (UESL) are extremely rare and continue to pose a diagnostic and therapeutic challenge. The aim of the study was to present a multicenter experience of the German CWS and Polish PPSTG groups in the treatment of UESL in children. PROCEDURE: Twenty-five patients were treated according to the CWS-96, CWS-2002, and CYVADIC protocols. Distant metastases were observed in four cases (16%). In four cases, an initial disease presentation mimicked other entities. A pure cystic appearance of liver mass led to misdiagnosis of hydatid cyst in three cases. In one case, laparotomy was performed due to the signs of appendicitis, and bleeding from ruptured liver tumor was found. All these patients were finally diagnosed as UESL. RESULTS: Thirteen patients received preoperative chemotherapy. Partial response was observed in 10 cases. Tumor resection was performed in 20 patients (primary resections, 12; delayed resections-, 8). In five patients, the primary tumor never became operable. The macroscopically complete resection rate was 95% (19/20). Postoperative chemotherapy was given to 20 children. Local radiotherapy was used in three children. After a median follow-up time of 136 months, 17 patients (68%) were alive with no evidence of disease. All children with unresectable tumor and three out of four patients with distant metastases died. The five-year overall survival (OS) rate was 72%. CONCLUSIONS: In summary, a complete tumor excision plays the central role in the treatment of UESL. A cystic presentation of the liver lesion on imaging does not exclude the diagnosis of malignant tumor.
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Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Sarcoma/diagnóstico , Sarcoma/terapia , Adolescente , Adulto , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Polonia , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
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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Bases de Datos Factuales , Hepatoblastoma , Neoplasias Hepáticas , Adolescente , Edad de Inicio , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Hepatoblastoma/diagnóstico , Hepatoblastoma/mortalidad , Hepatoblastoma/patología , Hepatoblastoma/terapia , Humanos , Incidencia , Lactante , Recién Nacido , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Masculino , Metástasis de la Neoplasia , Estudios Prospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
BACKGROUND & AIMS: Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Herein, we aimed to uncover the mechanisms of HB pathobiology and to identify new biomarkers and therapeutic targets in a move towards precision medicine for patients with advanced HB. METHODS: We performed a comprehensive genomic, transcriptomic and epigenomic characterization of 159 clinically annotated samples from 113 patients with HB, using high-throughput technologies. RESULTS: We discovered a widespread epigenetic footprint of HB that includes hyperediting of the tumor suppressor BLCAP concomitant with a genome-wide dysregulation of RNA editing and the overexpression of mainly non-coding genes of the oncogenic 14q32 DLK1-DIO3 locus. By unsupervised analysis, we identified 2 epigenomic clusters (Epi-CA, Epi-CB) with distinct degrees of DNA hypomethylation and CpG island hypermethylation that are associated with the C1/C2/C2B transcriptomic subtypes. Based on these findings, we defined the first molecular risk stratification of HB (MRS-HB), which encompasses 3 main prognostic categories and improves the current clinical risk stratification approach. The MRS-3 category (28%), defined by strong 14q32 locus expression and Epi-CB methylation features, was characterized by CTNNB1 and NFE2L2 mutations, a progenitor-like phenotype and clinical aggressiveness. Finally, we identified choline kinase alpha as a promising therapeutic target for intermediate and high-risk HBs, as its inhibition in HB cell lines and patient-derived xenografts strongly abrogated tumor growth. CONCLUSIONS: These findings provide a detailed insight into the molecular features of HB and could be used to improve current clinical stratification approaches and to develop treatments for patients with HB. LAY SUMMARY: Hepatoblastoma is a rare childhood liver cancer that has been understudied. We have used cutting-edge technologies to expand our molecular knowledge of this cancer. Our biological findings can be used to improve clinical management and pave the way for the development of novel therapies for this cancer.