Faculty Bibliography

INTRODUCTION: Liquid biopsy has the potential to revolutionize diagnosis and management of cancer. In brain tumors, detection of cell free tumor DNA (ctDNA) and circulating tumor cells (CTC) is challenging due to low level of the circulating material. We present a novel workflow for detection and capture of CTCs. METHODS: Peripheral blood was obtained from five pediatric patients with astrocytoma (n=2), ependymoma (n=1), dysembryoplastic neuroepithelial tumor (n=1), and medulloblastoma (n=1) at initial resection (n=3) and relapse (n=2). Samples were enriched using the Clear-Bridge ClearCell FX1 system and the suspension stained with antibodies against CD56 and CD45. Samples were analyzed using Silicon Biosystems DEPArray to capture single and pooled CTCs. CTCs were identified by CD56 positivity, while leukocytes were positive for CD45 and NK cells double-positive for CD56 and CD45. RESULTS: CTCs were identified in all 5 patient samples. The number of CD56-positive cells isolated from each sample ranged from 1 to 25 (mean 9). The CD56-positive cells were on average 11.8 mum in diameter (range 9.0-15.7 mum), and CD45-positive cells were on average 10.8 mum in diameter (range 8.9-15.9 mum). Single CTCs and CTC pools are amenable to molecular analysis after whole genome amplification. CONCLUSION: We report a novel integrated workflow for capturing CTCs in pediatric patients with brain tumors. While rare, CTCs circulate in peripheral blood of patients with brain tumors regardless of their grade and are amenable for molecular analysis. This method has the potential to serve as a non-invasive diagnostic and monitoring method for pediatric brain tumors

Program cell death ligand-1 (PD-L1) membranous expression on >5% tumor cells (PD-L1 positive tumors) is an unfavorable prognostic marker in many solid tumors. We previously showed that approximately 40% of neurofibromatosis type 2 (NF2) meningiomas are PD-L1 positive tumors. However, due to the invasive nature of biopsies, collection of tumor tissue is not always feasible. Thus, a non-invasive alternative is needed to evaluate the status of tumor growth and confirm PD-L1 positive tumors before the consideration of immunotherapy. It has recently been revealed that expression of PD-L1 on tumor associated macrophages is also a strong prognostic indicator. We retrieved formalin-fixed paraffin-embedded (FFPE) tissue from 10 NF2 meningioma cases to identify PD-L1 expression on macrophages and/or monocytes. We found that 3 out of 4 PD-L1 positive tumors were associated with expression of PDL-1 on CD68 (-) monocyte-like cells located in the peri-and intravascular lumens. These cells were only observed in 1 out of 6 PD-L1 negative tumors. Compared to others, tumors with PD-L1 expression on monocyte-like cells presented a higher Ki-67 proliferative index that was above 10%. Our results suggest that PD-L1 positive circulating CD68 (-) monocyte-like cells are correlated with tumor cell PD-L1 expression and progression in NF2 meningiomas

Although radiotherapy is the mainstay of treatment for children with diffuse intrinsic pontine gliomas (DIPG), fewer than 10% of patients survive past two years from diagnosis despite 30 years of clinical trials. ONC201 is an oral, selective DRD2 antagonist that induces p53-independent apoptosis and has been reported to produce a durable response in an adult with a H3 K27M mutant recurrent glioblastoma. In April 2017, a 33 month old female presented with headaches, right 6th nerve palsy and MRI findings consistent with a DIPG. A biopsy revealed an H3.3 K27M mutant glioblastoma. A patient-derived DIPG tumorsphere cell line was created from the biopsy sample and in vitro studies revealed a potent reduction in cell viability following 5 days of treatment with ONC201, with an IC50 of approximately 600nM. She received involved field irradiation (54Gy). Starting one month following irradiation, single agent, oral ONC201 125mg (11mg/kg) was given weekly on a compassionate use protocol. An MRI, 4 months later revealed stable disease. Clinically, her 6th nerve palsy and left hemiparesis have improved. She is otherwise asymptomatic. Pharmacokinetic studies are being analyzed. She has had no side effects detected. Based on our in vitro and clinical findings as well as other experience in vitro and in adults, ONC201 is currently being investigated with a phase 1 trial in pediatric patients with H3 K27M mutant gliomas

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