Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma.

Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.

Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma.

In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.

Desmoplastic Infantile Ganglioglioma: A MAPK Pathway-Driven and Microglia/Macrophage-Rich Neuroepithelial Tumor.

MAPK pathway activation has been recurrently observed in desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA) with reported disproportionally low mutation allele frequencies relative to the apparent high tumor content, suggesting that MAPK pathway alterations may be subclonal. We sought to expand the number of molecularly profiled cases and investigate if tumor cell composition could account for the observed low mutation allele frequencies. Molecular (targeted neuro-oncology next-generation sequencing/RNA sequencing and OncoScan microarray) and immunohistochemical (CD68-PGM1/CD163/CD14/CD11c/lysozyme/CD3/CD20/CD34/PD-L1) studies were performed in 7 DIG. Activating MAPK pathway alterations were identified in 4 (57%) cases: 3 had a BRAF mutation (V600E/V600D/V600_W604delinsDQTDG, at 8%-27% variant allele frequency) and 1 showed a TPM3-NRTK1 fusion. Copy number changes were infrequent and nonrecurrent. All tumors had at least 30% of cells morphologically and immunophenotypically consistent with microglial/macrophage lineage. Two subtotally resected tumors regrew; 1 was re-excised and received adjuvant treatment (chemotherapy/targeted therapy), with clinical response to targeted therapy only. Even with residual tumor, all patients are alive (median follow-up, 83 months; 19-139). This study further supports DIG as another MAPK pathway-driven neuroepithelial tumor, thus expanding potential treatment options for tumors not amenable to surgical cure, and suggests that DIG is a microglia/macrophage-rich neuroepithelial tumor with frequent low driver mutation allele frequencies.

Case-based review: atypical teratoid/rhabdoid tumor.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare CNS cancer that typically occurs in children younger than 3 years of age. Histologically, AT/RTs are embryonal tumors that contain a rhabdoid component as well as areas with primitive neuroectodermal, mesenchymal, and epithelial features. Compared to other CNS tumors of childhood, AT/RTs are characterized by their rapid growth, short symptomatic prodrome, and large size upon presentation, often leading to brain compression and intracranial hypertension requiring urgent intervention. For decades, the mainstay of care has been a combination of maximal safe surgical resection followed by adjuvant chemotherapy and radiotherapy. Despite advances in each of these modalities, the relative paucity of data on these tumors, their inherently aggressive course, and a lack of molecular data have limited advances in treatment over the past 3 decades. Recent large-scale, multicenter interdisciplinary studies, however, have significantly advanced our understanding of the molecular pathogenesis of these tumors. Multiple clinical trials testing molecularly targeted therapies are underway, offering hope for patients with AT/RT and their families.

Cross-Cultural Medical Care Training and Education: a National Survey of Pediatric Hematology/Oncology Fellows-in-Training and Fellowship Program Directors.

Pediatric hematologists/oncologists face complex situations such as breaking bad news, treatment/clinical trials discussions, and end-of-life/hospice care. With increasing diversity in patient and physician populations, cultural competency and sensitivity training covering different aspects of pediatric hematology/oncology (PDHO) care can help improve health care delivery and reduce disparities. Though it is considered a required component of fellowship training, there is no clearly defined curriculum meant specifically for PDHO fellows-in-training (PDHO-F). A national online survey of 356 PDHO-F and 67 PDHO program directors (PDHO-PD) was conducted to assess the educational experience, perceptions about identifying barriers including one's own biases and trainee comfort in delivering culturally sensitive care in various PDHO relevant clinical situations. One hundred and eleven (31.2%) PDHO-F and 27 (40.3%) PDHO-PD responded. 30.6% of PDHO-F "strongly agreed/agreed" they received comprehensive cross-cultural communication (CCC) training. The top two teaching methods were faculty role modeling and informal teaching. Majority of CCC training is in medical school or residency and only 10.8% of PDHO-F reported that most of their CCC training was in fellowship. In most clinical situations, there was a modest direct correlation between the fellow's level of agreement that they received comprehensive CCC training and their comfort level. Comfort level with some clinical situations was also significantly different based on year of training. Fellowship training programs should have CCC curricula which use experiential learning models and lay the foundation for promoting cultural awareness, self-reflection, and better patient-physician partnerships which can eventually adapt to and surmount the challenges unique to the physician's chosen field of practice.

Obesity, sedentary lifestyle, and video games: The new thrombophilia cocktail in adolescents.

Rates of venous thromboembolism have increased in the adolescent population over the last two decades, likely due to advanced diagnostics, increased use of central venous catheters, chronic medical conditions, obesity, and oral contraceptive use. Of these factors, a modifiable risk factor for adolescents is obesity. Sedentary lifestyle and prolonged immobilization are additional prothrombotic risk factors that are often associated with obesity. With ever-increasing screen time, sedentary behavior has risen accordingly, especially among gamers. We present four cases of adolescents who developed life-threatening venous thromboembolic events in the setting of obesity, sedentary lifestyle and/or immobilization, and prolonged video game use.

Recurrent copy number alterations in low-grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation.

Pleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy-number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A-PXA), 23 BRAF V600E mutant tumors (61%). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n = 33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50%-60%) (37). CDKN2A/B deletion was present in similar proportion of PXA (83%), A-PXA (93%), BRAF V600E (87%), and wild-type (87%) tumors. Whole chromosome gains/losses were frequent, including gains +7 (n = 15), +2 (n = 11), +5 (n = 10), +21 (n = 10), +20 (n = 9), +12 (n = 8), +15 (n = 8), and losses -22 (n = 11), -14 (n = 7), -13 (n = 5). Losses and copy-neutral loss of heterozygosity were significantly more common in A-PXA, involving chromosomes 22 (P = 0.009) and 14 (P = 0.03). Amplification of 8p and 12q was identified in a single tumor. Histologic grade was a robust predictor of overall survival (P = 0.003), while other copy-number changes, including CDKN2A/B deletion, did not show significant association with survival. Distinct histologic patterns of anaplasia included increased mitotic activity in an otherwise classic PXA or associated with small cell, fibrillary, or epithelioid morphology, with loss of SMARCB1 expression in one case. In 10 cases, matched specimens were compared, including A-PXA with areas of distinct low- and high-grade morphology (n = 2), matched primary/tumor recurrence (n = 7), or both (n = 1). Copy-number changes on recurrence/anaplastic transformation were complex and highly variable, from nearly identical profiles to numerous copy-number changes. Overall, we confirm CDKN2A/B deletion as key a feature of PXA not associated with tumor grade or BRAF mutation, but central to the underlying genetics of PXA.

Management of pediatric hepatocellular carcinoma: A multimodal approach.

HCC is rare in the pediatric population, but is the second most common liver malignancy in children. Survival rates for primary unresectable HCC have been dismal. The objective of this study was to describe our experience with a multimodal approach for the management of unresectable HCC in two adolescent patients and to review the literature. Both patients are currently alive with no recurrence at 51 and 29 months post-transplant. Multimodality treatment involving chemotherapy with doxorubicin, cisplatin, and sorafenib; TACE; timely liver transplantation; and post-transplant therapy with sorafenib and mTOR inhibitors may help improve outcomes and prolong survival in pediatric patients with unresectable HCC.

Intertumoral Heterogeneity within Medulloblastoma Subgroups.

While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

A retrospective review of pediatric antiphospholipid syndrome and thrombosis outcomes.

: Pediatric antiphospholipid syndrome (APS) is characterized by vascular thromboses and multisystem involvement associated with persistently positive antiphospholipid antibodies testing. There is limited literature regarding risk factors for development of thrombosis and long-term thrombotic outcomes in pediatric APS. The objective of our study was to review our institutional experience with pediatric APS and thrombosis outcomes. We conducted a 20-year retrospective review to study the clinical features, management, and long-term outcomes of patients between ages 6 months and 18 years diagnosed with APS. Seventeen patients (7 female; 10 male), with median age at first thrombosis being 15.3 years (range: 0.63-17.98 years) were included. The median follow-up period was 4.3 years (range: 0.8-16.9 years). Venous thrombosis was noted in 11 patients (64.7%) with arterial events occurring in six patients (35.3%). Nine (53%) patients were noted to have primary APS. Recurrent and/or progressive thrombotic events occurred in 10 patients (58.8%), which is higher than reported literature. The median time for recurrence/progression was 1.4 years (range: 0.37-11.85 years). At the time of recurrence/progression, only two (20%) patients were at therapeutic levels of anticoagulation. The high recurrence rate with majority of patients not being on therapeutic levels of anticoagulation at the time of the event along with 60% of recurrent events occurring at least 1 year from first vascular event suggests the possible need for long-term anticoagulation. However, larger pediatric studies are required to assess the need for long-term/indefinite anticoagulation.

Molecular Modeling and Functional Analysis of Exome Sequencing-Derived Variants of Unknown Significance Identify a Novel, Constitutively Active FGFR2 Mutant in Cholangiocarcinoma.

PURPOSE: Genomic testing has increased the quantity of information available to oncologists. Unfortunately, many identified sequence alterations are variants of unknown significance (VUSs), which thus limit the clinician's ability to use these findings to inform treatment. We applied a combination of in silico prediction and molecular modeling tools and laboratory techniques to rapidly define actionable VUSs. MATERIALS AND METHODS: Exome sequencing was conducted on 308 tumors from various origins. Most single nucleotide alterations within gene coding regions were VUSs. These VUSs were filtered to identify a subset of therapeutically targetable genes that were predicted with in silico tools to be altered in function by their variant sequence. A subset of receptor tyrosine kinase VUSs was characterized by laboratory comparison of each VUS versus its wild-type counterpart in terms of expression and signaling activity. RESULTS: The study identified 4,327 point mutations of which 3,833 were VUSs. Filtering for mutations in genes that were therapeutically targetable and predicted to affect protein function reduced these to 522VUSs of interest, including a large number of kinases. Ten receptortyrosine kinase VUSs were selected to explore in the laboratory. Of these, seven were found to be functionally altered. Three VUSs (FGFR2 F276C, FGFR4 R78H, and KDR G539R) showed increased basal or ligand-stimulated ERK phosphorylation compared with their wild-type counterparts, which suggests that they support transformation. Treatment of a patient who carried FGFR2 F276C with an FGFR inhibitor resulted in significant and sustained tumor response with clinical benefit. CONCLUSION: The findings demonstrate the feasibility of rapid identification of the biologic relevance of somatic mutations, which thus advances clinicians' ability to make informed treatment decisions.

Neonatal renal vein thrombosis: role of anticoagulation and thrombolysis--an institutional review.

Neonatal renal vein thrombosis (NRVT) is a rare thromboembolic complication in the neonatal period, and sequelae from renal dysfunction can cause significant morbidity. The authors retrospectively reviewed 10 patients with NRVT treated at their institution. The majority of the cohort were male (n = 9), preterm (n = 6), and had unilateral NRVT (n = 6). Six patients received thrombolysis and/or anticoagulation, and 4 patients received supportive care only. Two of the 6 patients treated with anticoagulation who had bilateral NRVT and anuria received thrombolysis with low-dose tissue plasminogen activator. Thrombolysis was not associated with any major adverse events, and both patients had marked improvement of renal function. Eight patients subsequently developed renal atrophy (3 received anticoagulation, 2 received thrombolysis with anticoagulation, and 3 received supportive care). Anticoagulation/thrombolysis did not appear to prevent renal atrophy. The role of thrombolysis needs to be further studied and considered in the setting of bilateral NRVT and acute renal failure.

Acute appendicitis in acute leukemia and the potential role of decitabine in the critically ill patient.

Acute appendicitis in children with acute leukemia is uncommon and often recognized late. Immunocompromised host state coupled with the importance of avoiding treatment delays makes management additionally challenging. Leukemic infiltration of the appendix though rare must also be considered. Although successful conservative management has been reported, surgical intervention is required in most cases. We present our experience with acute appendicitis in children with acute leukemia and a case of complete remission of acute myeloid leukemia with a short course of decitabine. Decitabine may serve as bridging therapy in critically ill patients who are unable to undergo intensive chemotherapy.

Advances in the management of low-grade gliomas.

Low-grade gliomas (LGGs) represent the most common childhood brain tumors and are a histologically heterogenous group of tumors. Most LGGs are surgically resectable with excellent 10-year overall survival outcomes of more than 90 % with surgery alone. Tumors not amenable to surgical resection and those with an aggressive biology are more challenging to treat. Conventional radiotherapy is a more efficacious method of long-term tumor control than chemotherapy. However, radiation is associated with significant cognitive, endocrine, and cerebrovascular late effects, making chemotherapy an often-preferred modality over radiotherapy, especially in younger children. Multiple chemotherapy regimens have been evaluated over the past few decades with comparable survival outcomes and differing toxicity profiles. Newer regimens containing antiangiogenic agents also show promise. Recent molecular studies have implicated the BRAF oncogene, a key regulator of the MAPK pathway, and the AKT/mTOR pathway in pediatric LGG tumorigenesis. This has opened up promising new avenues for targeted therapy, with many agents currently under investigation.

Cumulative cisplatin dose is not associated with event-free or overall survival in children with newly diagnosed average-risk medulloblastoma treated with cisplatin based adjuvant chemotherapy: report from the Children's Oncology Group.

BACKGROUND: Survival rates for children with medulloblastoma have risen over the past decade, in part due to the addition of cisplatin-containing adjuvant chemotherapy. Total dose of cisplatin required for optimal treatment is unknown. The purpose of this study was to evaluate the survival outcomes based on cumulative cisplatin doses (CCD) in children with newly diagnosed average-risk medulloblastoma. PROCEDURE: CCD data were reviewed for 363 patients in a prospective study evaluating patients between 3 and 21 years with a newly diagnosed average-risk medulloblastoma and treated with craniospinal radiation and post-radiation cisplatin based adjuvant chemotherapy. RESULTS: Eight-year event-free survival (EFS) and overall survival (OS) estimates were 78.2 ± 2.6% and 83.9 ± 2.4%, respectively. Only 73 patients received the protocol specified CCD of 600 mg/m(2), primarily due to mandated cisplatin toxicity-related dose reductions. The median CCD given to those without relapse or death on treatment was 487.5 mg/m(2). CCD, as a time-dependent covariate, was not associated with EFS (P = 0.54) or OS (P = 0.11). The 343 patients who completed chemotherapy failure-free were categorized into four groups according to CCD (n = 10; 75-150 mg/m(2)), (n = 26; 151-300 mg/m(2)), (n = 113; 301-450 mg/m(2)), and (n = 194; 451-600 mg/m(2)). There were no statistically significant differences in distributions of EFS (P = 0.53) or OS (P = 0.49) among these four groups. CONCLUSION: CCD is not associated with EFS or OS suggesting that lower doses of cisplatin may be incorporated into future medulloblastoma trials, thereby limiting its toxicity profile without affecting survival. If ototoxicity is encountered, more stringent cisplatin dose modification/cessation rules seem warranted.

Bilateral temporal bone langerhans cell histiocytosis: radiologic pearls.

Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder with an unpredictable clinical course and highly varied clinical presentation ranging from single system to multisystem involvement. Although head and neck involvement is common in LCH, isolated bilateral temporal bone involvement is exceedingly rare. Furthermore, LCH is commonly misinterpreted as mastoiditis, otitis media and otitis externa, delaying diagnosis and appropriate therapeutic management. To improve detection and time to treatment, it is imperative to have LCH in the differential diagnosis for unusual presentations of the aforementioned infectious head and neck etiologies. Any lytic lesion of the temporal bone identified by radiology should raise suspicion for LCH. We hereby describe the radiologic findings of a case of bilateral temporal bone LCH, originally misdiagnosed as mastoiditis.

Biologically targeted therapeutics in pediatric brain tumors.

Pediatric brain tumors are often difficult to cure and involve significant morbidity when treated with traditional treatment modalities, including neurosurgery, conventional chemotherapy, and radiotherapy. During the past two decades, a clearer understanding of tumorigenesis, molecular growth pathways, and immune mechanisms in the pathogenesis of cancer has opened up promising avenues for therapy. Pediatric clinical trials with novel biologic agents are underway to treat various pediatric brain tumors, including high and low grade gliomas and embryonal tumors. As the therapeutic potential of these agents undergoes evaluation, their toxicity profiles are also becoming better understood. These agents have potentially better central nervous system penetration and lower toxicity profiles compared with conventional chemotherapy. In infants and younger children, biologic agents may prove to be of equal or greater efficacy compared with traditional chemotherapy and radiation therapy, and may reduce the deleterious side effects of traditional therapeutics on the developing brain. Molecular pathways implicated in pediatric brain tumors, agents that target these pathways, and current clinical trials are reviewed. Associated neurologic toxicities will be discussed subsequently. Considerable work is needed to establish the efficacy of these agents alone and in combination, but pediatric neurologists should be aware of these agents and their rationale.