Successful Treatment of Refractory or Relapsed Hepatoblastoma With Autologous Hematopoietic Stem Cell Transplantation in Children.

BACKGROUND: The standard-risk hepatoblastoma has a good prognosis in children; however, refractory or relapsed (R/R) hepatoblastoma has a poor prognosis and high mortality rate. This study aimed to demonstrate the efficacy of high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT) rescue in pediatric patients with R/R hepatoblastoma. METHODS: We retrospectively analyzed 6 pediatric patients with R/R hepatoblastoma who underwent autologous HSCT. The MEC conditioning regimen was used for all patients, comprising melphalan 140 mg/m 2 /day intravenously (IV) on day 7 and 70 mg/m 2 on day 6, etoposide 200 mg/m 2 IV on days 5 to 8, and carboplatin 400 mg/m 2 IV on days 5 to 8. One patient received a TopoThioCarbo regimen, comprising topotecan 2 mg/m 2 /day IV on days 4 to 8, thiotepa 300 mg/m 2 /day IV on days 6 to 8, and carboplatin 500 mg/m 2 /day IV on days 3 to 5, as the conditioning regimen for the first transplantation. This was followed by salvage chemotherapy for relapse, and the second transplantation was performed using MEC as the conditioning regimen. RESULTS: We report the retrospective results of 6 patients with a median age of 1.8 (range 0.4 to 10.2) years who had R/R hepatoblastoma and underwent autologous HSCT. The median follow-up period was 58 (range 28 to 113) months after diagnosis. The median stage at diagnosis was 2.0 (range 2 to 4). Two patients had lung metastases during diagnosis. The median initial alpha-fetoprotein level was 292,888 (range 28,831 to 2,406,942) ng/mL, and the median number of chemotherapy lines before autologous HSCT was 3.5 (range 2 to 7). The disease status before HSCT was complete remission (CR) for all patients. The engraftment rate was 100%. No treatment-related mortality was reported. The 3-year event-free survival and overall survival rates were 83.3% and 100%, respectively. One patient relapsed after the second HSCT and achieved CR after salvage chemotherapy. CONCLUSION: This study suggests autologous HSCT as an effective treatment in pediatric patients with R/R hepatoblastoma. Nevertheless, future large-scale prospective studies are warranted.

Children's Hepatic Tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) System for Pediatric Patients with Hepatoblastoma: A Retrospective, Hospital-Based Cohort Study in South Korea.

PURPOSE: In 2017, the Children's Hepatic Tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) system was introduced. We aimed to evaluate the accuracy of CHIC-HS System for the prediction of event-free survival (EFS) in Korean pediatric patients with hepatoblastoma. MATERIALS AND METHODS: This two-center retrospective study included consecutive Korean pediatric patients with histopathologically confirmed hepatoblastoma from March 1988 through September 2019. We compared EFS among four risk groups according to the CHIC-HS system. Discriminatory ability of CHIC-HS system was also evaluated using optimism-corrected C-statistics. Factors associated with EFS were explored using multivariable Cox regression analysis. RESULTS: We included 129 patients (mean age, 2.6±3.3 years; female:male, 63:66). The 5-year EFS rates in the very low, low, intermediate, and high-risk groups, according to the CHIC-HS system were 90.0%, 82.8%, 73.5%, and 51.3%, respectively. The CHIC-HS system aligned significantly well with EFS outcomes (p=0.004). The optimism-corrected C index of CHIC-HS was 0.644 (95% confidence interval [CI], 0.561 to 0.727). Age ≥ 8 (vs. age ≤ 2; hazard ratio [HR], 2.781; 95% CI, 1.187 to 6.512; p=0.018), PRE-Treatment EXTent of tumor (PRETEXT) stage IV (vs. PRETEXT I or II; HR, 2.774; 95% CI, 1.228 to 5.974; p=0.009), and presence of metastasis (HR, 2.886; 95% CI, 1.457 to 5.719; p=0.002), which are incorporated as the first three nodes in the CHIC-HS system, were independently associated with EFS. CONCLUSION: The CHIC-HS system aligned significantly well with EFS outcomes in Korean pediatric patients with hepatoblastoma. Age group, PRETEXT stage, and presence of metastasis were independently associated with EFS.

Small Cell Undifferentiated Histology Does Not Adversely Affect Outcome in Hepatoblastoma: A Report From the Children's Oncology Group (COG) AHEP0731 Study Committee.

PURPOSE: Small cell undifferentiated (SCU) histology in hepatoblastoma (HB) tumors has historically been associated with a poor prognosis. Tumors from patients enrolled on Children's Oncology Group (COG) study AHEP0731 underwent institutional and central pathologic review for identification of SCU histology. PATIENTS AND METHODS: Patients with SCU histology identified at the local treating institution who had otherwise low-risk tumors were upstaged to the intermediate-risk treatment stratum, whereas those only identified by retrospective central review were treated per the local institution as low-risk. Patients with otherwise intermediate- or high-risk tumors remained in that treatment stratum, respectively. Central review was to be performed for all tissue samples obtained at any time point. Treatment was per local review, whereas analysis of outcome was based on central review. RESULTS: Thirty-five patients had some elements (1%-25%) of SCU identified on central review of diagnostic specimens. All but two patient tissue sample retained nuclear INI1 expression. The presence of SCU histology did not correlate with age, alpha-fetoprotein level at diagnosis, or sex. The presence of SCU did not affect event-free survival (EFS). EFS at 5 years for patients with low-risk, intermediate-risk, and high-risk with SCU HB was 86% (95% CI, 33 to 98), 81% (95% CI, 57 to 92), and 29% (95% CI, 4 to 61), respectively, compared with EFS at 5 years for patients without SCU enrolled with low-risk, intermediate-risk, and high-risk of 87% (95% CI, 72 to 95), 88% (95% CI, 79 to 94), and 55% (95% CI, 32 to 74; P = .17), respectively. CONCLUSION: The presence of SCU histology in HB does not appear to adversely affect outcome. Future studies should be able to treat patients with SCU HB according to risk stratification without regard to the presence of SCU histology.

Recent improvement in survival outcomes and reappraisal of prognostic factors in hepatoblastoma.

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.

A new risk-stratification system for hepatoblastoma in children under six years old and the significance for prognosis evaluation-a 14-year retrospective study from a single center.

BACKGROUND: This study explores and analyzes the clinical characteristics and prognostic factors of hepatoblastoma (HB) in children under 6 years old and establishes a new risk-stratification system for individualized therapy. METHODS: The clinical data of 382 pediatric patients under 6 years old (231 males and 151 females) who had been diagnosed with HB by pathology between May 2005 and May 2019 were collected. By analyzing the risk factors influencing the survival rate of patients with HB, a new risk-stratification system was established, and it was compared with previous risk-stratification systems by a receiver operating characteristic (ROC) curve. RESULTS: (1) According to a Kaplan-Meier survival analysis, the one-year, three-year, and five-year overall survival (OS) was 93.7, 84.0, and 73.9%, respectively, and the event-free survival (EFS) was 90.5, 79.2, and 67.5%, respectively. (2) The independent risk factors influencing prognosis in pediatric patients with HB were alpha-fetoprotein (AFP) < 100 ng/ml or > 1000 ng/ml (HR = 3.341, P = 0.005); platelet count > 400 × 109/L (pooled hazard ratio [HR] = 2.123, P = 0.026); PRETEXT stage IV (HR = 4.026, P = 0.001); vascular involvement (HR = 2.178, P = 0.019); distant metastasis (HR = 2.634, P = 0.010);and multifocality (HR = 2.215, P = 0.012). (3) A new risk-stratification system was established and divided into three groups: low risk, moderate risk, and high risk. There were statistical differences among the three groups (P = 0.002). Compared with the previous risk-staging systems, there was no significant difference in the survival rate. Although the effect in the guiding therapy was the same, the area under the curve for the ROC curve was 0.835 (95% CI: 0.784-0.885) for the new stratification system. CONCLUSION: This new risk-stratification system had a better predictive value for the prognosis of pediatric patients with HB than other stratification systems.

Management of hepatoblastoma in the United States: Can we do better?

BACKGROUND: Hepatoblastoma is the most common type of liver cancer in children. Refined therapeutic approaches combining risk-adapted chemotherapy along with complete tumor resection has led to improved survival. We aimed to evaluate the current state of management and outcomes for hepatoblastoma in the United States. METHODS: We retrospectively reviewed 794 children (<18 years) with hepatoblastoma from the National Cancer Database (2004-2015). We assessed overall survival by means of Kaplan-Meier method, log-rank tests, and multivariable Cox regression. RESULTS: Median age was 1 year (interquartile range: 0-2) and 170 (21.4%) presented with metastatic disease. Surgical resection was included in the treatment of 614 (77.3%) children (resection in 66.8% and liver transplantation in 10.6%). In the entire cohort, 95.1% of children received chemotherapy. In the surgical cohort, 575 (93.6%) received chemotherapy (34.5% neoadjuvant, 28.7% adjuvant, 30.5% both neoadjuvant and adjuvant). The 5-year overall survival was 76.6% for the entire cohort (no-surgery group: 55.3% vs surgery group: 82.8%). In multivariable analysis for all children, age ≥8 years (P = .009), metastasis (P < .001), surgery only (P = .009), and chemotherapy only (P < .001) were risk factors for mortality. In multivariable analysis for the surgical cohort, metastasis (P = .001), multifocality (P = .02), no chemotherapy (P = .03), and margin-positive resection (P = .02) were risk factors for mortality. CONCLUSION: Excellent long-term overall survival is achievable with a combination of chemotherapy and surgical resection when a negative resection margin is achieved. However, nearly a quarter of children never received surgical treatment, representing a potential opportunity for improvement in care.

Feasibility of Nonanatomical Liver Resection in Diligently Selected Patients with Hepatoblastoma and Comparison of Outcomes with Anatomic Resection.

INTRODUCTION: Treatment guidelines for hepatoblastoma discourage nonanatomic liver resections. However, the evidence for this is inadequate and comes from a study performed almost two decades ago which additionally contained inherent limitations. This study aimed to assess the feasibility and oncologic outcomes of nonanatomic resections (NAR) performed in diligently selected patients and compare the results with anatomic resections (AR). MATERIALS AND METHODS: A total of 120 patients who underwent liver resections for hepatoblastoma between January 2008 and July 2019 were reviewed. Feasibility of NAR was based on postchemotherapy relations to vessels, site of the lesion, and possibility of achieving negative resection margins. RESULTS: AR was performed in 95 patients and 25 had NAR. The NAR cohort had similar International Childhood Liver Tumors Strategy Group (SIOPEL) risk group distribution. Blood loss and operative times were lower in patients undergoing NAR. No differences were noted between the two groups concerning postoperative morbidity and hospitalization. There were no pathologic positive margins or local recurrences in the NAR patients. Relapse free (RFS) and overall survival (OS) was similar in the two groups (p = 0.54 and 0.96, respectively). Subgroup analysis of only posttreatment extent of tumor (POSTTEXT) I and II patients also showed no difference in RFS or OS for the two groups with a persistent significant difference in operative times and blood loss. CONCLUSION: NAR is feasible with clear margins in carefully selected patients. It is not associated with more complications and outcomes are not inferior to AR. NAR is associated with lesser blood loss and operative time.

Temporal trends in childhood cancer survival in Egypt, 2007 to 2017: A large retrospective study of 14 808 children with cancer from the Children's Cancer Hospital Egypt.

Childhood cancer is a priority in Egypt due to large numbers of children with cancer, suboptimal care and insufficient resources. It is difficult to evaluate progress in survival because of paucity of data in National Cancer Registry. In this study, we studied survival rates and trends in survival of the largest available cohort of children with cancer (n = 15 779, aged 0-18 years) from Egypt between 2007 and 2017, treated at Children's Cancer Hospital Egypt-(CCHE), representing 40% to 50% of all childhood cancers across Egypt. We estimated 5-year overall survival (OS) for 14 808 eligible patients using Kaplan-Meier method, and determined survival trends using Cox regression by single year of diagnosis and by diagnosis periods. We compared age-standardized rates to international benchmarks in England and the United States, identified cancers with inferior survival and provided recommendations for improvement. Five-year OS was 72.1% (95% CI 71.3-72.9) for all cancers combined, and survival trends increased significantly by single year of diagnosis (P < .001) and by calendar periods from 69.6% to 74.2% (P < .0001) between 2007-2012 and 2013-2017. Survival trends improved significantly for leukemias, lymphomas, CNS tumors, neuroblastoma, hepatoblastoma and Ewing Sarcoma. Survival was significantly lower by 9% and 11.2% (P < .001) than England and the United States, respectively. Significantly inferior survival was observed for the majority of cancers. Although survival trends are improving for childhood cancers in Egypt/CCHE, survival is still inferior in high-income countries. We provide evidence-based recommendations to improve survival in Egypt by reflecting on current obstacles in care, with further implications on practice and policy.

High expression of IGF2-derived intronic miR-483 predicts outcome in hepatoblastoma.

BACKGROUND: The role of microRNAs (miRs) as biomarkers to predict outcome in hepatoblastoma (HB), the most common malignant liver tumor in childhood, has still to be determined. Recently, the so-called four-miR signature has been described to efficiently stratify HB patients according to their prognosis. OBJECTIVE: We examined the recently described four-miR signature for its clinical relevance in an independent validation cohort of HB patients and tried to optimize its predictive value by analyzing four additional miRs involved in HB biology. METHODS: Expression of eight miR was determined in 29 tumor and 10 normal liver samples by TaqMan assays and association studies and Kaplan-Meier estimators determined their clinical relevance. RESULTS: Stratifying HB patients by the four-miR signature showed no difference in patients' outcome, which was also reflected by the lack of association with any clinical risk parameter. Adding miR-23b-5p and miR-23b-3p did also not increase its discriminating power. However, the integration of miR-483-5p and miR-483-3p into the four-miR signature could predict patients with poor outcome that were associated with large tumors and vessel invasive growth with high accuracy. CONCLUSIONS: The expansion of the four-miR signature by miR-483 serves as a useful biomarker to predict outcome of HB patients.

Outcomes for high-risk hepatoblastoma in a resource-challenged setting.

BACKGROUND: Outcomes of high-risk hepatoblastoma have been dismal, especially in resource-challenged countries where access to chemotherapy and paediatric liver transplantation is limited for the underprivileged. This study aimed to assess the results of treatment of high-risk hepatoblastoma in a tertiary centre, including patients who had non-transplant surgical procedures in the form of extended resection. METHODS: A review of patients with high-risk hepatoblastoma treated between January 2012 and May 2018 was carried out. Perioperative data and long-term outcomes were analysed. RESULTS: Of 52 children with hepatoblastoma, 22 were considered to have high-risk hepatoblastoma (8 girls and 14 boys). The mean(s.d.) age at diagnosis was 35(20) months. Of these 22 children, five died without surgery. Of the remaining 17 who underwent surgery, six had a resection (4 right and 2 left trisectionectomies) and 11 underwent living-donor liver transplantation. Median follow-up was 48 (range 12-90) months. Thirteen of the 17 children were alive at last follow-up and four developed disseminated disease (3 had undergone liver transplantation and 1 liver resection). The overall survival rate at 1, 3 and 5 years was 77, 64 and 62 per cent for the whole cohort with high-risk hepatoblastoma. In children who had surgery, 1-, 3- and 5-year survival rates were 91, 82 and 73 per cent for transplantation and 100, 83 and 83 per cent for resection. There was no difference in survival between the two surgical groups. CONCLUSION: Excellent results in the treatment of high-risk hepatoblastoma are possible, even in resource-challenged countries.

ANTECEDENTES: Los resultados del hepatoblastoma de alto riesgo (high risk hepatoblastoma, HRH) han sido pésimos, especialmente en países con recursos limitados, donde el acceso a la quimioterapia y al trasplante hepático pediátrico es limitado para los menos privilegiados. Este estudio tuvo como objetivo evaluar los resultados del HRH en un centro de tercer nivel, incluyendo a los pacientes que se sometieron a procedimientos quirúrgicos diferentes del trasplante en forma de resecciones extendidas. MÉTODOS: Se realizó una revisión de los pacientes con HRH tratados entre enero del 2012 y mayo de 2018. Se analizaron los datos perioperatorios y los resultados a largo plazo. RESULTADOS: De 52 niños con hepatoblastomas, 22 fueron considerados HRH (8 pacientes del sexo femenino/14 del sexo masculino). La edad media al diagnóstico fue de 35 ± 20 meses. De estos 22 pacientes, cinco fallecieron sin haber sido intervenidos quirúrgicamente. De los 17 restantes que se sometieron a cirugía, en seis se realizaron resecciones (4 trisectorectomías derechas, 2 trisectorectomías izquierdas) y 11 se sometieron a un trasplante de hígado de donante vivo. La mediana de seguimiento fue de 48 meses (12-90 meses). Trece de 17 niños estaban vivos en el último seguimiento, y cuatro habían desarrollado enfermedad diseminada (3 habían sido sometidos a trasplante hepático y 1 a resección hepática). La supervivencia global a 1, 3 y 5 años fue del 77,3%, 63,6% y 62% para toda la cohorte de HRH. Entre los que se sometieron a cirugía, las supervivencias a 1, 3 y 5 años fueron del 90,9%, 81,8% y 72,7% para el trasplante y del 100%, 83,3% y 83,3% para la resección. No hubo diferencia en la supervivencia entre los dos grupos sometidos a cirugía. CONCLUSIÓN: En países con recursos limitados es posible obtener excelentes resultados en el tratamiento de HRH.

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.

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.

Outcome and Late Complications of Hepatoblastomas Treated Using the Japanese Study Group for Pediatric Liver Tumor 2 Protocol.

PURPOSE: We report here the outcomes and late effects of the Japanese Study Group for Pediatric Liver Tumors (JPLT)-2 protocol, on the basis of cisplatin-tetrahydropyranyl-adriamycin (CITA) with risk stratification according to the pretreatment extent of disease (PRETEXT) classification for hepatoblastoma (HB). PATIENTS AND METHODS: From 1999 to 2012, 361 patients with untreated HB were enrolled. PRETEXT I/II patients were treated with up-front resection, followed by low-dose CITA (stratum 1) or received low-dose CITA, followed by surgery and postoperative chemotherapy (stratum 2). In the remaining patients, after 2 cycles of CITA, responders received the CITA regimen before resection (stratum 3), and nonresponders were switched to ifosfamide, pirarubicin, etoposide, and carboplatin (ITEC; stratum 4). Intensified chemotherapeutic regimens with autologous hematopoietic stem-cell transplantation (SCT) after resection were an optional treatment for patients with refractory/metastatic disease. RESULTS: The 5-year event-free and overall survival rates of HB patients were 74.2% and 89.9%, respectively, for stratum 1, 84.8% and 90.8%%, respectively, for stratum 2, 71.6% and 85.9%%, respectively, for stratum 3, and 59.1% and 67.3%%, respectively, for stratum 4. The outcomes for CITA responders were significantly better than those for nonresponders, whose outcomes remained poor despite salvage therapy with a second-line ITEC regimen or SCT. The late effects, ototoxicity, cardiotoxicity, and delayed growth, occurred in 61, 18, and 47 patients, respectively. Thirteen secondary malignant neoplasms (SMNs), including 10 leukemia, occurred, correlating with higher exposure to pirarubicin and younger age at diagnosis. CONCLUSION: The JPLT-2 protocol achieved up-front resectability in PRETEXT I/II patients with no annotation factors, and satisfactory survival in patients who were CITA responders in the remaining patients. However, outcomes for CITA nonresponders were unsatisfactory, despite therapy intensification with ITEC regimens and SCT. JPLT-2 had a relatively low incidence of cardiotoxicity but high rates of SMNs.

Clinical risk stratification of children with SIOPEL high-risk hepatoblastoma in Taiwan.

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.

Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications.

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.

Knockdown of otubain 2 inhibits liver cancer cell growth by suppressing NF-κB signaling.

The deubiquitinase otubain 2 (OTUB2) has been reported to play significant roles in the tumorigenesis of several cancers, but the role of OTUB2 in liver cancer is not investigated yet. In the present study, OTUB2 was found significantly upregulated in liver cancer tumor tissues and cell lines, and elevated OTUB2 indicated as a negative index for the overall survival of liver cancer patients. At the cellular level, knockdown of OTUB2 markedly inhibited liver cancer cell growth. Our further investigations revealed that knockdown of OTUB2 significantly suppressed NF-κB-driving luciferase activity, and markedly inhibited the phosphorylation of NF-κB p65 in liver cancer cells, which indicated that OTUB2 mediated liver cancer cell growth by regulating NF-κB signaling. Additionally, we found that liver cancer cell lines harboring higher OTUB2 expression were more sensitive to NF-κB inhibitors, and overexpression of OTUB2 could significantly reduce the antitumor effects of NF-κB inhibitors in liver cancer cells. This study indicated that OTUB2 could be a promising target for the treatment of liver cancer in the future.

Novel treatment of refractory / recurrent pulmonary hepatoblastoma.

BACKGROUND: There is no consensus about how to manage pulmonary metastasis in patients with hepatoblastoma. We reviewed a treatment with a combination of oxaliplatin, vincristine, and topotecan (OVT) paired with radiofrequency ablation (RFA) of 12 patients with multiple refractory / recurrent pulmonary hepatoblastoma. METHODS: The medical records from patients with ≤21 years of age presenting with multiple deposits (≥2) of refractory / recurrent pulmonary hepatoblastoma were reviewed. The following data were extracted from each patient: age, gender, histological subtyping, cycles of OVT, tumor size, biomarkers, chemotherapy regimen and dosage, RFA details, treatment response, follow up, and patient outcomes. The primary outcome measure was the complete response (CR) of pulmonary diseases, and secondary outcomes were event-free survival rate and overall survival rate. RESULTS: Of 12 assessable patients, three (25%) (95% CI, 46.3-104) patients achieved PR (partial resopnse) after they finished OVT. After RFA, five (41.7%) (95% CI, 8.95-74.4) patients achieved CR (complete response). The 2 year event-free survival rate was 33% (95% CI, 20.5-64.6). The 2 year overall survival for the study group was 41.7% (95% CI, 8.9-74.4). All toxicity events were handled satisfactorily and no toxic related deaths were observed. CONCLUSIONS: Our review report shows that OVT combined with RFA can be a successful treatment modality for previously heavily treated refractory / recurrent pulmonary metastatic lesions from hepatoblastoma.

Impact of microscopically margin-positive resection on survival in children with hepatoblastoma after hepatectomy: a retrospective cohort study.

BACKGROUND: Impact of R1 (microscopically margin-positive) resection on survival of patients with hepatoblastoma (HB) remains debatable. This study aimed to compare the long-term outcomes of R0 (microscopically margin-negative) and R1 resection for HB in children after hepatectomy. METHODS: We retrospectively reviewed files of children with HB who underwent resection at our institution between September 1, 2005, and November 30, 2017. Survival analyses and prognostic factors were evaluated using Kaplan-Meier curves and Cox regression models. RESULTS: Of 259 patients, 218 (84.2%) underwent R0 and 41 (15.8%) R1 resection. After adjusting for confounding factors, R1 resection demonstrated non-significantly lower overall survival (OS: hazard ratio [HR] = 0.75; 95% CI 0.34-1.64) and shorter event-free survival (EFS: HR = 0.97; 95% CI 0.53-1.78) rates than R0 resection. However, stratified analysis showed significantly increased risk of poor OS and EFS in patients with metastasis and mixed epithelial/mesenchymal pathologic subtype in R1 compared with R0 resection (P values for interactions < 0.05). There was no significant difference between R0 resection with metastasis and R1 resection with metastasis in the incidence of local recurrence (P = 0.494); however, a significant difference in the incidence of local recurrence was seen between R0 and R1 resection for subgroups with mixed pathologic subtypes (P = 0.035). CONCLUSIONS: With effective chemotherapy, microscopic margin status may not be associated with survival outcome in children with HB undergoing hepatectomy. However, stratified analysis showed that R1 resection might be associated with decreased survival in children with mixed epithelial/mesenchymal HB, compared with R0 resection, and not affect survival outcomes in those with an epithelial subtype and without metastasis.

Immunohistochemical Expression Analysis of EpCAM in Hepatoblastomas.

The epithelial cell adhesion molecule (EpCAM) is involved in oncogenesis of hepatoblastomas (HBs). Prior genomic profiling studies showed higher EpCAM expression and worse prognosis in HBs containing primitive histotypes, however, this has not been fully addressed from an immunohistochemical perspective. Our goal is to characterize differential EpCAM immunohistochemistry (EpCAM-IHC) among HBs histotypes. We retrieved 62 HBs from 52 patients. EpCAM-IHC was performed (anti-MOC-31, 1:50 dilution; Cell Marque Corporation, Rocklin, CA) and graded in histotypes using the immunoreactive score. The median age of patients was 2 years (range: 0.4 to 9 y) with a M:F ratio of 1.9. Outcome information was available in 38 patients (alive=30, alive with disease=3, and deceased=5) with median follow-up of 60 months (range: 2 to 171 mo). EpCAM-IHC showed notable overexpression (immunoreactive score >4) in embryonal (89%) and crowded fetal (74%) in contrast to glandular (33%), well-differentiated fetal (32%), and small cell undifferentiated/blastemal (3%) components. Mesenchymal elements were negative. In summary, EpCAM-IHC is helpful to distinguish between epithelial components as it is progressively lost in the transition from embryonal to crowded fetal and into well-differentiated fetal histotypes. Its preferential expression among primitive HBs might have therapeutic and prognostic implications. The significance of its largely negative expression in small cell undifferentiated/blastema is interesting despite its presumed immaturity, deserving further studies.

Assessment of Survival of Pediatric Patients With Hepatoblastoma Who Received Chemotherapy Following Liver Transplant or Liver Resection.

Importance: The incidence of hepatoblastoma is increasing, and liver transplant (LT) provides a potential cure for pediatric patients with unresectable hepatoblastoma; however, the use of LT for hepatoblastoma has not been examined in a modern cohort. Moreover, data are lacking on the association between the type of surgical management received and overall risk of death among pediatric patients with hepatoblastoma. Objectives: To examine the receipt of LT among pediatric patients with hepatoblastoma and to assess overall survival of pediatric patients with hepatoblastoma who were treated with chemotherapy after LT or liver resection (LR) using data from a national cancer registry. Design, Setting, and Participants: This cohort study used data for 443 pediatric patients with histologically confirmed hepatoblastoma who received chemotherapy and surgical therapies, as documented in the Surveillance, Epidemiology, and End Results database of the National Cancer Institute, from 2004 to 2016, with follow-up through December 31, 2018. Multivariable logistic regression was used to determine factors associated with the use of LT. Cox proportional hazards models were used to assess factors associated with overall survival. Data analysis was performed from April 18, 2019, to July 25, 2019. Main Outcomes and Measures: Overall survival. Results: Among 443 patients receiving chemotherapy (mean [SD] age, 1.8 [2.6] years; 167 [37.7%] female), 350 (79%) underwent LR and 93 (21%) underwent LT. Multivariable analysis showed that patients with multiple lesions were more likely to undergo LT than LR (31% vs 13%; P < .001) and that patients with higher stage tumors were more likely to undergo LT than LR (local disease, 20% vs 58%; regional disease, 58% vs 24%; distant disease, 22% vs 18%; P < .001). There was a statistically significant 19% increase in the receipt of LT from 8% in 1998 to 27% 2016 (trend test, P = .02). Overall survival at 10 years was not significantly different for the 2 surgical management strategies (87.2% [95% CI, 78.3%-97.1%] for patients undergoing LT vs 87.8% [95% CI, 83.5%-92.4%] for those undergoing LR; P = .92). The overall risk of death was not significantly different for LT compared with LR (hazard ratio, 0.716; 95% CI, 0.309-1.657; P = .44). Conclusions and Relevance: The use of LT for the management of hepatoblastoma has increased significantly over time. Among pediatric patients with hepatoblastoma receiving chemotherapy, LT was not associated with improved overall survival compared with LR. There was no significant different between treatments with regard to the outcome variable, but this finding cannot be interpreted as indicating equivalence or lack of superiority.

Extensive Hepatectomy as an Alternative to Liver Transplant in Advanced Hepatoblastoma: A New Protocol Used in a Pediatric Liver Transplantation Center.

BACKGROUND: Surgery is a key factor in the treatment of hepatoblastoma, but choosing between an aggressive resection and liver transplant may be an extremely difficult task. The aim of this study was to describe the outcomes of patients with advanced hepatoblastoma: pretreatment extent of disease (PRETEXT)/post-treatment extent of disease (POST-TEXT) III and IV undergoing aggressive resections or living donor liver transplant in cases involving the entire liver. Based on this experience, a new protocol for the treatment of these patients was proposed. METHODS: A retrospective study included patients with advanced hepatoblastoma (POST-TEXT III and IV) who were referred for a liver transplant from 2010 to 2017. RESULTS: A total of 24 children were included: 13 (54.2%) were male, with a median age at diagnosis of 42 months (range, 15-120 months), and a history of prematurity was identified in 20.8% of the patients. Ten cases (41.7%) were staged as PRETEXT/POST-TEXT III, and 12 cases (50.0%) were staged as PRETEXT/POST-TEXT IV. Two patients were referred after posthepatectomy recurrence. Five patients underwent a liver transplant, with recurrence and death in 2 patients (40.0%) within a mean period of 6 months. In the extensive hepatectomy group, there was recurrence in 6 patients (31.6%), with disease-free outcomes and overall survival in 63.2% and 94.7% of patients, respectively. CONCLUSION: In cases of advanced hepatoblastoma, an extensive surgical approach is a valuable option. The fact that the team was fully prepared to proceed with living donor liver transplant allowed the surgeon to be more aggressive and to switch to transplantation when resection was not possible.