Abstract BACKGROUND Embryonal tumors with PLAGL1 and PLAGL2 amplification (ET, PLAGL) display substantial clinical heterogeneity regarding applied treatment and outcomes. As a recently-defined entity, the spectrum of tumor-driving PLAG-family alterations is not yet fully elucidated. METHODS We analyzed clinical and MRI data from patients with ET, PLAGL. Second, we identified and analyzed tumors with epigenetic similarities. RESULTS 18 patients with ET, PLAGL revealed diverse clinical behavior. Patients with PLAGL1-amplified tumors (ET, PLAGL1) were older (median 8 years), had a higher rate of complete resections (6/9) and fewer relapses (3/9). Patients with PLAGL2-amplified tumors (ET, PLAGL2) were younger (median 1.9 years), often incompletely resected (6/9) and prone to earlier relapse/progression. Five-year PFS was 89% and 17% (ET, PLAGL1/ET, PLAGL2), with no predictive value of initial surgical extent on PFS/OS. Postoperative treatment included chemotherapy (17/18, various protocols) alone (n=8) or combined with RT (n=9). The three survivors with ET, PLAGL2 underwent induction and high-dose chemotherapy. All five patients with less intensive chemotherapy relapsed. Most first and all subsequent ET, PLAGL2 relapses were distant, questioning the value of initial local radiotherapy. Two ET, PLAGL1 relapses occurred >8 years after diagnosis (one after, one without previous RT). Through methylation-based t-SNE we identified 143 tumors with epigenetic similarities to ET, PLAGL. Filtering revealed a core set of 27 tumors, of which seven displayed evidence of PLAG1-fusion events and one PLAG1-amplification. RNAseq analysis (n=4) revealed distinct gene fusions involving PLAG1, with similar genes upregulated (RET, CYP2W1 and imprinted genes) as in ET, PLAGL. Like ET, PLAGL, PLAG1-fused tumors, occurred in young children with different diagnoses and localizations. CONCLUSION PLAG1-fused tumors are epigenetically similar to ET, PLAGL, show similarities in gene expression, and need to be differentiated from neuroepithelial tumor with PLAGL1-fusion. Future investigations will examine differences in clinical behavior and the utility of PLAG1/L1/L2 IHC for diagnosis.
Deep venous thrombosis (DVT) has been previously reported in children with methicillin-resistant Staphylococcus aureus (MRSA). This study reviews our institutional experience by evaluating characteristics and outcomes of children with DVT and staphylococcal infections. Retrospective clinical data from 16 pediatric patients with DVT and staphylococcal infections over a 5-year period was obtained via medical record abstraction. Sixteen patients with a median age at diagnosis of 8 years were included. The most common infection encountered was osteomyelitis (56%). The most common isolated organism was MRSA (63%). Central venous catheters were present in 50% of cases. All patients received anticoagulation with low molecular weight heparin except 1 patient with superficial venous thrombosis who was managed conservatively. Fifty percent of patients had complete resolution of DVT by the end of treatment, 25% of the patients had early disappearance of the thrombus at 7 to 10 days. Only 2 patients (12.5%) had persistent thrombus at 6 months. Staphylococcal infections may increase the risk of DVT in children. Therefore, a high index of suspicion for DVT is warranted in children with Staphylococcal infections (particularly MRSA) to promptly diagnose, treat and minimize complications. Prophylactic anticoagulation in presence of staphylococcal infection, particularly MRSA, may be considered in future studies.
Metabolism of drugs in infants and young children is significantly different from older individuals due to differences in distribution, protein-binding capacity, hepatic metabolism and renal excretion. Body surface area (BSA) is used to dose chemotherapeutics in older children; however, this is inappropriate for infants and young children since it does not take into account the differences in extracellular water distribution. We describe four cases of sinusoidal obstruction syndrome (SOS) that occurred in young children while receiving induction chemotherapy with cisplatin, etoposide, vincristine, cyclophosphamide and high-dose methotrexate on the “Head Start (HS)” 4 clinical trial using BSA for dosing (mg/m2). Patients #1 and #2 were both 2-years old at diagnosis, received and tolerated the first two cycles with mg/kg dosing uneventfully, then turned 3-years old and received cycle #3 with mg/m2 dosing as per protocol guidelines, and developed SOS. Patient #3 was 3-years old at diagnosis, received induction chemotherapy with mg/m2 dosing, and developed SOS during the very first cycle. Patient #4 was 4-years old at diagnosis and received all 3 induction cycles with mg/m2 dosing, developed serious nephrotoxicity during cycle #1 followed by SOS during cycle #3. In contrast, none of the 40 patients treated on HS II protocol with identical chemotherapy regimen, but with mg/kg dosing, developed SOS. Caution should be exercised when dosing young children between 3-6 years of age by BSA. The HS 4 trial was amended and reopened after external, independent DSMB review to dose all chemotherapy drugs in children <6 years old with mg/kg dosing.
Introduction: High rates of patients require readmission to the hospital within 6 months of hematopoietic stem cell transplantation (HSCT). We investigated the relationship between readmission rates and outcomes after HSCT in children, adolescents, and young adults (CAYA). Materials and Methods: A retrospective analysis of patients (26 years or younger) treated with HSCT was conducted. Results: A chart review of 435 CAYA who underwent HSCT from 2008 to 2015 revealed that 171 patients (39%) had at least 1 hospital readmission within 180 days of transplant; 87% received allogeneic and 13% received autologous HSCT. A total of 312 readmission events were reported. The median follow-up time was 31 months. Documented infection (n=99) and graft-versus-host disease complications (n=60) were the most common causes. Higher than 2 readmission rates were associated with lower overall survival (OS) ( P =0.001) and disease-free survival ( P <0.001) in patients who received allogeneic HSCT. These findings were not found in the autologous HSCT. In a multivariate analysis of those who received allogeneic HSCT, prior treatment with ≥2 chemotherapy regimens ( P =0.03) was independent predictor of lower OS. There were also trends noted toward lower OS for patients with documented infections at index admission or subsequent readmissions ( P =0.09). Conclusions: More than 2 hospital readmissions within 6 months of allogeneic HSCT in CAYA, who are either heavily pretreated or had documented infections at index admission or subsequent readmissions adversely affected the outcomes.
Hematopoietic stem cell transplantation (HSCT) provides potential curative treatment for various benign and malignant conditions. However, there is a high rate of patients requiring readmission to the hospital within six months of transplantation. There is only limited literature evaluating risk factors and causes of readmission of children, adolescents and young adults (AYA) who underwent HSCT.
Children with rare, relapsed or refractory cancers often face limited treatment options, and few predictive biomarkers are available that can enable personalized treatment recommendations. The implementation of functional precision medicine (FPM), which combines genomic profiling with drug sensitivity testing (DST) of patient-derived tumor cells, has potential to identify treatment options when standard-of-care is exhausted. The goal of this prospective observational study was to generate FPM data for pediatric patients with relapsed or refractory cancer. The primary objective was to determine the feasibility of returning FPM-based treatment recommendations in real time to the FPM tumor board (FPMTB) within a clinically actionable timeframe (<4 weeks). The secondary objective was to assess clinical outcomes from patients enrolled in the study. Twenty-five patients with relapsed or refractory solid and hematological cancers were enrolled; 21 patients underwent DST and 20 also completed genomic profiling. Median turnaround times for DST and genomics were within 10 days and 27 days, respectively. Treatment recommendations were made for 19 patients (76%), of whom 14 received therapeutic interventions. Six patients received subsequent FPM-guided treatments. Among these patients, five (83%) experienced a greater than 1.3-fold improvement in progression-free survival associated with their FPM-guided therapy relative to their previous therapy, and demonstrated a significant increase in progression-free survival and objective response rate compared to those of eight non-guided patients. The findings from our proof-of-principle study illustrate the potential for FPM to positively impact clinical care for pediatric and adolescent patients with relapsed or refractory cancers and warrant further validation in large prospective studies. ClinicalTrials.gov registration: NCT03860376 .
Though diffuse gliomas arising in the thalamus of children frequently harbor K27M mutation in the histone H3 genes H3F3A or HIST1H3B, children with diffuse gliomas involving the bilateral thalami at presentation often lack histone H3 mutations (Broniscer et al, Brain Pathology 2018). In order to investigate the molecular pathogenesis of pediatric bithalamic diffuse gliomas, we performed comprehensive genetic profiling of seven cases (ages 3–11 years). Six tumors (86%) harbored mutations in the EGFR oncogene in the absence of accompanying EGFR amplification. Four of these EGFR mutations were small in-frame insertions/duplications within exon 20 that encodes a portion of the intracellular tyrosine kinase domain, where mutations are common in lung adenocarcinoma and fibrous hamartoma of infancy but are not typically present in gliomas. The other two cases with EGFR mutations were located in the extracellular ligand-binding domain, where mutations and rearrangements are common in IDH-wildtype glioblastomas in the cerebral hemispheres of adults. Additional pathogenic alterations included TP53 mutation (n=4 cases), CDKN2A homozygous deletion (1), CDK6 amplification (1), CDKN2C mutation (1), TERT promoter mutation (1), HIST1H3B K27M mutation (1), and truncating mutations involving the BCOR (1), BCORL1 (2), LZTR1 (1), and CREBBP (1) transcriptional regulatory genes. No tumors harbored pathogenic alterations involving the H3F3A, HIST1H3C, SETD2, PDGFRA, MET, PPM1D, ACVR1, FGFR1, BRAF, PTPN11, IDH1, IDH2, MYB, and MYBL1 genes. In comparison, EGFR mutations are rare (<1% of 982 cases) in pediatric high-grade gliomas in general (Mackay et al, Cancer Cell 2017). Together, these findings identify pediatric bithalamic diffuse gliomas as a unique subtype of IDH-wildtype and mostly histone H3-wildtype high-grade glioma characterized by frequent EGFR kinase domain mutations, with implications for precision medicine treatment using small molecule kinase inhibitors such as poziotinib, a CNS-penetrant agent with selective activity against exon 20 mutant EGFR.
Pediatric malignancies in adults, in contrast to the same diseases in children are clinically more aggressive, resistant to chemotherapeutics, and carry a higher risk of relapse.Molecular profiling of tumor sample using next generation sequencing (NGS) has recently become clinically available.We report the results of targeted exome sequencing of six adult patients with pediatric-type malignancies : Wilms tumor(n=2), medulloblastoma(n=2), Ewing's sarcoma( n=1) and desmoplastic small round cell tumor (n=1) with a median age of 28.8 years .Detection of druggable somatic aberrations in tumors is feasible.However, identification of actionable target therapies in these rare adult patients with pediatric-type malignancies is challenging.Continuous efforts to establish a rare disease registry are warranted.
