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- Furqan Shaikh (Canada)
- Dora Correia (Switzerland)
Introduction
- Dora Correia (Switzerland)
- Furqan Shaikh (Canada)
HISTOLOGIC SUBTYPE PREDICTS DISPARATE OUTCOMES IN PEDIATRIC HEPATOCELLULAR CARCINOMA – A PEDIATRIC SURGICAL ONCOLOGY RESEARCH COLLABORATIVE STUDY
- Scott S. Short (United States of America)
Abstract
Background and Aims
Hepatocellular carcinoma (HCC) is a rare cancer in children with variant histologic subtypes. There are a paucity of reliable data to guide clinical expectations and predict prognosis. To allow for characterization of clinical outcomes of variant histologic HCC subtypes, a multi-institutional collaborative dataset was developed.
Methods
Patients (0-20 years) with HCC (1990-2018) were identified at 15 hospitals participating in the Pediatric Surgical Oncology Research Collaborative (PSORC). Clinical data collected included demographics, staging, treatment and outcomes. Patients were subdivided into the following histologic subtypes: HCC with or without underlying liver disease, fibrolamellar carcinoma (FLC), and hepatoblastoma with HCC features (HB-HCC). Univariate and multivariate analyses were used to identify predictors of mortality and clinical outcomes.
Results
262 children were identified with hepatocellular neoplasms: 110 HCC (69 normal liver, 34 inflammatory/cirrhotic, 7 unknown); 119 FLC; and 32 HB-HCC. We found notable differences in clinical presentation and behavior amongst tumor subtypes, including an increase in lymph node involvement in FLC and higher PRETEXT stage in HCC. Factors associated with mortality (p<0.05) included HCC, elevated AFP, multifocality, and PRETEXT stage. Multivariate analysis identified increased risk of mortality for HCC vs FLC (HR 2.2, p=0.004) and in patients deemed unresectable (HR 3.45, p<0.001). Achievement of disease-free status at any point predicted survival (HR 0.15, p <0.001.)
Conclusions
This large pediatric HCC dataset allows comprehensive analysis of outcomes for patients with these rare cancers. Our data demonstrate that pediatric HCC subtypes should not be considered equivalent entities, as FLC and HCC present with different anatomic patterns and differential outcomes. This dataset will be used as a foundation to elucidate the impact of histologic characteristics on specific outcomes, with the goal of designing optimal risk-stratified treatment algorithms for these patients.
THE OUTCOMES OF LIVING DONOR LIVER TRANSPLANTATION FOR HEPATOBLASTOMA IN JAPAN: AN ANALYSIS OF CASES LISTED IN THE REGISTRY OF THE JAPANESE LIVER TRANSPLANTATION SOCIETY
- Hajime Uchida (Japan)
Abstract
Background and Aims
Liver transplantation (LT) has been increasingly performed for unresectable hepatoblastoma (HB) with acceptable results. We conducted a national survey of cases undergoing living donor liver transplantation (LDLT) for HB to evaluate their outcomes.
Methods
We conducted a national survey of patients undergoing LDLT for HB between October 1990 and April 2018 and the cases were followed until December 2019. We mainly analyzed the impact of tumor recurrence and lung metastasis before LT on outcomes.
Results
Ninety-eight patients (61 males and 37 females with a median age at LDLT of 3.0 years) underwent LDLT during the study period. A total of 30 of 98 (30.6%) patients received salvage liver transplantation, including 25 patients for recurrent tumor and 5 patients for deteriorating liver function after liver resection. There was no significant difference in the 1- and 5-year patient survival rates between patients undergoing primary LT and those who received salvage LT for tumor recurrence (89.7%, 81.6% vs. 88.0%, 76%) (P = 0.526). Of the 68 patients who received primary LT, 21 had lung metastases. Among these 21 patients, complete radiographic clearance of lung metastases was achieved in 10 at the time of LT, while the remaining 11 required metastasectomy before LT. New lesions appeared in the lungs of two patients during neoadjuvant chemotherapy. On comparing the prognosis by the presence of lung metastases, the recurrence rate was significantly worse in the patients with lung metastases at the time of the diagnosis than in those without lung metastases (P=0.043), whereas there was no marked difference in the mortality rate (P=0.742). The mortality rate tended to be higher in patients with the appearance of lung metastasis during NAC than in others (P=0.086).
Conclusions
LT can be curative for unresectable HB, including cases with lung metastases and after recurrence.
TARGETING ONCOGENIC MICRORNAS IN MALIGNANT GERM CELL TUMOURS WITH LOCKED NUCLEIC ACID (LNA)-BASED INHIBITORS.
- Shivani Bailey (United Kingdom)
Abstract
Background and Aims
MicroRNAs (miRNAs) are short, non-protein-coding RNAs that regulate gene expression, primarily through mRNA degradation. We have shown that all malignant germ-cell-tumours (mGCTs) overexpress two miRNA clusters, miR-371~373 and miR-302/367, resulting in downregulation of functionally significant mRNAs/pathways. Here, we inhibited these overexpressed miRNAs in mGCT cells in vitro to determine their functional significance and explore their potential role as therapeutic targets.
Methods
RT-qPCR confirmed that miR-371~373 and miR-302/367 levels in mGCT cell lines [seminoma (SEM), yolk sac tumour (YST) and embryonal carcinoma (EC)] corresponded to those in tissue samples of the relevant tumour subtype. MiRNA inhibitors composed primarily of locked nucleic acids (LNAs) were designed to target key mature miRNAs. Gene expression profiling of cells treated with inhibitor or control was performed using mRNA microarray. Sylamer analysis was used to identify direct mRNA targets of these miRNAs, and key pathways analysed using KEGG and Reactome for functional validation.
Results
Targeting mature miRNAs of the miR-302 family (miR-302a-d) using LNA-based inhibitors resulted in reproducible growth inhibition in SEM and YST cells, although EC cells were more resistant to treatment. In the mGCT cells with reduced growth, Sylamer revealed enrichment of upregulated mRNAs that contained the seed-complementary-region for miR-302a-d in their 3’ untranslated regions. Pathway analysis of these upregulated mRNA targets primarily demonstrated involvement in cell cycle regulation. This was functionally validated through cell cycle analysis using flow cytometry.
Conclusions
LNA-based miR-302 family inhibition results in cell cycle arrest in two main subtypes of mGCT and may represent a new therapeutic approach.
RISK OF GERM CELL TUMORS IS INCREASED IN CHILDREN WITH BIRTH DEFECTS
- Jeremy M. Schraw (United States of America)
Abstract
Background and Aims
Some studies indicate that birth defects are associated with germ cell tumors (GCTs). However, few investigations have evaluated associations by histologic subtype, location, age at diagnosis, sex, and type of birth defect. Therefore, we leveraged a large cohort of children diagnosed with GCTs to perform a detailed analysis of the associations between birth defects and these malignancies.
Methods
Cases (N=638) were participants in the Children’s Oncology Group GaMETES Study, diagnosed with GCTs between July 2008 and December 2015 and aged <20 years. Controls matched on sex and maternal race/ethnicity were randomly selected from births in three U.S. states (Oklahoma, North Carolina, and Texas) at a 10:1 ratio. Information on birth defects diagnoses were obtained from parental interview (cases) and statewide birth defects registries (controls). Logistic regression was used to calculate odds ratios and 95% confidence intervals (ORs; 95% CIs) to estimate the association between birth defects and GCTs, overall and by subtype.
Results
Overall, the prevalence of birth defects and chromosomal anomalies in GCT cases was 8% compared to 4% in controls (2.0, 1.4-2.7). Non-chromosomal defects were associated with mixed/other GCTs (1.9, 1.0-3.3) and yolk sac tumors (1.9, 0.8-3.9). Genitourinary defects were associated with yolk sac tumors (3.4, 1.0-8.6), gonadal tumors (2.2, 0.9-4.5), and extracranial/extragonadal tumors (2.2, 0.5-6.0). In stratified analyses, associations with non-chromosomal defects were stronger among males, but increased odds of yolk sac (2.1; 0.6-5.4) and extracranial/extragonadal tumors (1.7; 0.4-4.8) were also observed among females.
Conclusions
Our results suggest that non-chromosomal birth defects, particularly genitourinary defects, are associated with GCTs in children and adolescents. Associations were strongest for yolk sac or mixed/other tumors, and may be specific to males. These findings could be leveraged to assist in the discovery of risk factors for these tumors and to understand sex ratio disparities.