Faculty Bibliography

We previously reported an increased prevalence of pre-treatment lymphopenia in pediatric patients with medulloblastoma, the most common childhood malignant brain tumor, suggesting tumor-induced systemic immune suppression present at the time of diagnosis. Tumor-induced systemic immune suppression, including lymphopenia, has been recognized in adult high-grade gliomas for several decades. Pediatric midline gliomas express distinct epigenetic and genetic alterations, such as the histone H3 K27M mutation. Patients with this mutation often experience a more aggressive clinical course and poor outcome. We confirmed the K27M mutation from tumor biopsies in 10 pediatric midline glioma patients by whole genome DNA methylation array analysis, and analyzed complete blood counts (CBC) at the time of diagnosis prior to surgery and chemotherapy. Compared to a control group of pilocytic astrocytoma, patients with K27M-mutated gliomas have higher monocyte-to-lymphocyte ratios (MLR) and absolute monocyte counts (AMC), reaching statistical significance (p<0.05). Furthermore, the prevalence of monocytosis, characterized by AMC above normal age-adjusted means, was statistically significantly higher (p<0.05) in the study group (80%) than the control group (33%). High pre-operative MLR has previously been reported in various solid tumors in association with worse prognosis and poor overall survival. This is the first study to our knowledge that identifies MLR as a potential valuable biomarker in pediatric gliomas. Our findings suggest monocytosis and overall tumor-induced systemic immune suppression present at the time of diagnosis in K27M mutant tumors. Aberrant circulating immune cell ratios may affect the development of immune therapies for malignant pediatric midline gliomas with the histone H3 K27M mutation

BACKGROUND: The optimal management of young children with newly-diagnosed supratentorial ependymomas remains poorly-defined. We report outcomes of young children under 7 years old at diagnosis prospectively treated on three sequential multi-center trials of intensive chemotherapy with intent of avoiding irradiation. METHODS: Between 1991 and 2009, 14 children (median/mean ages of 34 months, range 3-74 months) were enrolled on "Head Start" (HS) trials (3 on HS-I, 3 on HS-II and 8 on HS-III). Induction chemotherapy was identical on HS-I and HS-II; on HSIII, this regimen was supplemented with high-dose systemic methotrexate in each cycle. Consolidation was uniform with a single cycle of marrowablative thiotepa/etoposide/carboplatin followed by autologous hematopoietic cell rescue. Irradiation was reserved for children >72 months old or with residual disease following Induction. Tumor pathology underwent central review. RESULTS: Ten children achieved initial gross total resections (GTRx) of tumor and 4 subtotal resections 2 of whom achieved GTRx following chemotherapy. Pathology revealed cellular ependymoma in 6 and anaplastic ependymoma in 8. There was 1 toxic death in Induction, on HS-I. Four children relapsed (3 on HS-II, 1 on HS-III), all locally, 3 expiring of disease despite focal irradiation, 20-72 months from initial diagnosis; the fourth continues recurrence-free after GTRx and focal irradiation. Seven patients survive without irradiation. CONCLUSIONS: Young children with supratentorial ependymomas have a good survival outcome when treated with irradiation-avoiding chemotherapy incorporating high-dose systemic methotrexate. However, it remains unclear if similar results could have been achieved with GTRx alone. The prognostic significance of molecular subtype is under evaluation

BACKGROUND: Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. METHODS: We analyzed pediatric and adult pineoblastoma samples (n=23) using integrated genomic studies, including genome-wide DNA methylation profiling, whole-exome or whole-genome sequencing, and whole-transcriptome analysis. RESULTS: Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower grade pineal tumors and normal pineal gland. Recurrent somatic mutations were found in genes involved in PKA-and NF-kappaB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expression of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain. Whole-transcriptome analysis showed that homozygous loss of DROSHA led to distinct changes in RNA expression profile. Disruption of the DROSHA locus in human neural stem cells using the CRISPR/Cas9 system, led to decrease of the DROSHA protein, and massive loss of miRNAs. CONCLUSION: We identified recurrent homozygous deletions of DROSHA in pineoblastoma, suggesting that different mechanisms disrupting miRNA processing are involved in the pathogenesis of familial versus sporadic pineoblastoma. Furthermore, a novel microduplication of PDE4DIP leading to upregulation of DUF1220 protein suggests DUF1220 as a novel oncogenic driver in pineoblastoma

BACKGROUND:The purpose of this study was to determine the feasibility and tolerability of tandem courses of high-dose thiotepa with autologous hematopoietic cell rescue (AHCR) in patients with recurrent, refractory solid tumors who were ineligible for a single course of high-dose therapy due to greater than minimal residual disease. Patients with decreased hearing or poor renal function were eligible. PROCEDURE/METHODS:Thiotepa was administered intravenously at a dose of 200 mg/m2 /day (6.67 mg/kg/day) daily for 3 days followed by AHCR. A second course of thiotepa was given 4 weeks later provided blood counts recovered sufficiently without evidence of tumor progression. RESULTS:Fifty-eight patients received 96 courses. Thirty-eight (65%) patients received two courses of therapy. Twenty-seven courses (28%) were administered completely in the outpatient setting. A toxic mortality rate of 3.4% was observed. Five of 26 patients with medulloblastoma were alive at a median of 35 months, whereas 21 patients died at a median of 11.7 months. Four of five patients with central nervous system germ cell tumors (CNS GCT) were alive 68-103 months following AHCR. CONCLUSIONS:Two cycles of high-dose thiotepa with AHCR were well tolerated even in these heavily pretreated patients. This therapy may provide prolonged survival in patients with recurrent malignant brain tumors, particularly medulloblastoma and CNS GCT.

Introduction Mucosal damage secondary to cancer therapy occurs in 30% of patients receiving standard chemotherapy and 80% of patients receiving high dose chemotherapy. Mucositis is painful, interferes with nutrition, hydration, and often causes delay or reduction in chemotherapy. 20%of CLABSIs at NYU Langone Health (NYULH) in 2015 were secondary to mucosal translocation Objectives The goal of the NYULH Interprofessional Mucositis Workgroup is to decrease the incidence of mucositis in adult and pediatric oncology patients. Methods An interprofessional team of inpatient and outpatient, adult and pediatric medical providers, dentists, nurse practitioners, nurses, pharmacists, and IT collaborated to develop a standardized NYULH mucositis guideline for prevention and treatment. Results An evidenced-based standardized guideline for mucositis prevention and treatment across adult and pediatric inpatient and outpatient was developed. Conclusions This project suggests that interprofessional collaboration is an effective strategy for development and implementation of a standardized guideline for both pediatric and adult inpatients and outpatients