5-year overall survival rates have surpassed 90% for childhood acute lymphocytic leukaemia, but survivors are at risk for permanent health sequelae. Although event-free survival appropriately represents the outcome for cancers with poor overall survival, this metric is inadequate when cure rates are high but challenged by serious, persistent complications. Accordingly, a group of experts in paediatric haematology-oncology, representative of 17 international acute lymphocytic leukaemia study groups, launched an initiative to construct a measure, designated severe toxicity-free survival (STFS), to quantify the occurrence of physician-prioritised toxicities to be integrated with standard cancer outcome reporting. Five generic inclusion criteria (not present before cancer diagnosis, symptomatic, objectifiable, of unacceptable severity, permanent, or requiring unacceptable treatments) were used to assess 855 health conditions, which resulted in inclusion of 21 severe toxicities. Consensus definitions were reached through a modified Delphi process supplemented by two additional plenary meetings. The 21 severe toxicities include severe adverse health conditions that substantially affect activities of daily living and are refractory to therapy (eg, refractory seizures), are without therapeutic options (eg, blindness), or require substantially invasive treatment (eg, cardiac transplantation). Incorporation of STFS assessment into clinical trials has the potential to improve and diversify treatment strategies, focusing not only on traditional outcome events and overall survival but also the frequencies of the most severe toxicities. The two major aims of this Review were to: prioritise and define unacceptable long-term toxicity for patients with childhood acute lymphocytic leukaemia, and define how these toxicities should be combined into a composite quantity to be integrated with other reported outcomes. Although STFS quantifies the clinically unacceptable health tradeoff for cure using childhood acute lymphocytic leukaemia as a model disease, the prioritised severe toxicities are based on generic considerations of relevance to any other cancer diagnosis and age group.

Background: IKZF1deletion is an unfavorable factor in Philadelphia negative (Ph ‐) B‐cell acute lymphoblastic leukemia. However, the effects of IKZF1 deletions co‐existing genetic alterations in Ph (‐) ALL have not been extensively studied.Methods: Bone marrow samples from 368 children with Ph (‐) ALL were analyzed by using multiplex ligation‐dependent probe amplification kit for detection of gene deletions and Sanger sequencing for mutational analysis of RAS pathway genes. The outcome was analyzed on 215 patients treated with Taiwan Pediatric Oncology Group‐ALL‐2002 protocol.Results: IKZF1 deletions were present in 12.8% and IKZF1^plus in 6.3% of patients. Mutations of RAS pathway genes were detected in 25.0% of IKZF1‐deleted patients. The 10‐year event‐free survival (EFS) of IKZF1‐undeleted patients was significantly better compared with IKZF1‐deleted patients (80.0% vs. 47.8%, p = 0.001). Compared with outcome of patients harboring IKZF1 deletion alone, no difference in EFS was observed in patients with IKZF1^plus, whereas three patients carried both IKZF1 and ERG deletions had a superior 10‐year EFS (100%). The 10‐year EFS of patients with any gene mutation of RAS pathway was worse than that of patients with wild‐type genes (79.1% vs. 61.6%, p = 0.033). In multivariate analysis, RAS pathway mutations and IKZF1 deletion were independent predictors of inferior EFS. Co‐existence of IKZF1 deletion with RAS pathway mutations had a worst 10‐year EFS (11.1 ± 10.5%) and 10‐year OS (53.3 ± 17.6%).Conclusions: Our results showed that RAS pathway mutation is an added‐value biomarker in pediatric IKZF1‐deleted Ph (‐) ALL patients.

Pediatric extracranial germ cell tumors (GCTs) are rare, accounting for approximately 3.5% of childhood cancers. Since the introduction of platinum-based chemotherapy, the survival rate of patients has improved to more than 80%. However, poor-risk subtypes of pediatric extracranial GCTs do not respond well to chemotherapy, leading to refractory or relapsed (R/R) diseases. For example, long-term survival rates of mediastinal GCTs or choriocarcinoma are less than 50%. According to reports in recent years for adult patients with R/R GCTs, the use of high-dose chemotherapy (HDCT) combined with autologous stem cell transplantation (ASCT) has clinical advantages; however, HDCT combined with ASCT has rarely been reported in pediatric GCTs. The R/R and poor-risk groups of pediatric GCTs could benefit from HDCT and ASCT.

Hepatoblastoma (HB) is the most common childhood primary hepatic malignancy. The overall survival rate in patients with HB has reached more than 80% over the past decades. The poor prognostic and high-risk HB have been defined, but the treatment and cure of refractory or relapsed HB is still an arduous task. The complete records of HB in patients under the age of 18 at the MacKay Memorial Hospital between 1990 and 2019 were examined. The treatment results for 11 patients with refractory or relapsed HB are presented. The multi-modality treatment records were reviewed and the clinical characteristics associated with poor outcome included multifocal lesions, low α-fetoprotein, great vessel invasion and metastases. Delayed liver tumor surgery was carried out in eight cases. The median duration of follow-up for the 11 patients was 48.6 months (range 1.9 to 316.8 months). The 5-year and 10-year overall survival rate were 62.3% ± 15% (SE) and 49.9% ± 16.4% (SE), respectively. Most treatment-related toxicities were tolerable. The major concern during long term follow-up was irreversible high-frequency hearing loss. Patients with refractory/relapsed HB are still a thorny issue and more research is needed to improve the outcome.