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Case Presentation A 3-year-old female with insignificant past medical history presented with 6 weeks of headaches, emesis, and lethargy. MR imaging identified a heterogeneously enhancing right cerebellar hemispheric mass and obstructive hydrocephalus. Gross total resection was performed without complications; pathology revealed classical WHO grade 4 medulloblastoma (MB). MR imaging of the spine and cerebrospinal fluid testing were negative for disseminated disease. Treatment for standard risk medulloblastoma was initiated, comprising proton craniospinal irradiation with posterior fossa boost and concurrent vincristine, followed by adjuvant chemotherapy with vincristine, lomustine, cisplatin, and cyclophosphamide as standard of care. Next generation sequencing of the tumor tissue performed using a high-multiplex PCR-based NGS panel was negative for alteration of the SMO, PTCH1 and CTBNN1 genes. Further molecular characterization via methylation profiling demonstrated the sonic hedgehog (SHH) molecular subtype. Prior to initiation of chemotherapy, renal ultrasound was performed and identified congenitally absent right kidney; audiology evaluation was unremarkable. Discussion In patients with Gorlin syndrome, cases of unilateral renal agenesis in association with germline SHH-pathway mutations have been reported [1]. SHH signaling is implicated in multiple steps in the development of the urinary system [2]. Outside Gorlin syndrome, however, to the best of our knowledge unilateral renal agenesis coinciding with SHH-driven MB has not been reported. Our patient notably lacks any clinical stigmata of Gorlin syndrome (skeletal abnormalities, skin pits, macrocephaly) and does not exhibit the characteristic germline genetic abnormalities that define GS (PTCH1 mutation or 9q22.3 microdeletion). There are important treatment implications for patients with the constellation of abnormalities we describe here, particularly regarding the requisite frequent monitoring of renal function during multi-agent chemotherapy courses. Our patient tolerated chemoradiation well, and is currently on maintenance chemotherapy with favorable course to date.

Purpose of Review Chemotherapy-induced nausea and vomiting (CINV) is a common cause of acute morbidity that impacts quality of life in children receiving cancer treatment. Here, we review the evolution of CINV prophylaxis guidelines in children, with an emphasis on the literature published in the last 5 years, to bring the reader up to date. Recent Findings Recent studies have led to the adoption of the “triple therapy” regimen of antiemetic prophylaxis (a 5-HT3 antagonist, dexamethasone, and a neurokinin-1 antagonist) as the backbone of recommendations for the prevention of CINV in children. Areas of new data include the addition of aprepitant and inclusion of palonosetron as a non-inferior 5-HT3 antagonist. In addition, there are emerging pediatric data informing patient-derived risk factors associated with CINV risk and classification of antineoplastic drugs based on emetogenicity. Summary Several recent pediatric studies have shaped published guidelines for CINV prophylaxis in children.

Tumors escape immune surveillance by activating the inhibitory checkpoint programmed death 1 (PD-1)/programmed death ligand 1 (PDL-1) pathway to attenuate T cell responses and render them functionally exhausted. Antibodies targeting the PD-1/PDL-1 immune checkpoint pathway rescue anti-tumor function and have shown remarkable success in treating several adult cancers, with PDL-1 positive tumors demonstrating the most objective responses. There are limited data on PDL-1 expression in pediatric central nervous system (CNS) tumors. We evaluated PDL-1 expression in formalin-fixed, paraffin-embedded tumor specimens from 37 pediatric patients via immunohistochemistry. We used a rabbit anti-human monoclonal anti PDL-1 antibody by Spring BioSciences (M4424). PDL-1+ positivity was quantified as either 50% membrane staining. Tumors with >5% membrane staining were scored as positive. The proportion of PDL-1+ tumors was 100% for anaplastic pleomorphic xanthoastrocytoma (4/4), 80% for pilocytic astrocytoma (4/5), 67% for glioblastoma (4/6), 67% for ependymoma (2/3), 50% for anaplastic astrocytoma (1/2), 50% for primitive neuroectodermal tumor (1/2), 25% for medulloblastoma (1/4), and 0% for pineoblastoma (0/6). Of the remaining 5 tumors tested, 2 were PDL-1+ (anaplastic ganglioglioma, anaplastic oligodendroglioma), and 3 were negative for PDL-1 expression (recurrent astrocytoma, atypical choroid plexus papilloma, choroid plexus carcinoma). Interestingly, all glioblastoma tumors (4/4) had >50% PDL-1 expression, whereas all pineoblastoma (6/6) tumors had

OBJECTIVES/SPECIFIC AIMS: To characterize the CD4+ T-cell response during CTLA-4 blockade immunotherapy with ipilimumab in patients with metastatic melanoma by correlating cytokine profiles with phenotypic changes in the intratumoral lymphocyte compartment of tumor biopsies obtained before and after treatment. METHODS/STUDY POPULATION: Peripheral blood mononuclear cell samples were obtained from patients with metastatic melanoma undergoing monotherapy with ipilimumab via the Interdisciplinary Melanoma Cooperative Group at New York University Langone Medical Center. We isolated CD4+ T-cells and used a cytometric bead array assay following in vitro activation with anti-CD3, anti-CD28 antibodies to characterize cytokine expression profiles by quantifying IFN gamma, IL-2, IL-4, IL-6, IL-10, IL-17, and TNF-α at 5 time points during therapy. In total, 53 peripheral blood samples were included from 12 patients. To correlate cytokine profiles with CD4+ T-cell phenotypes in the intratumoral lymphocyte compartment, multiplex immunofluorescence was performed using CD4, CD8, CCR7, CD45RO, and FOXP3 antibodies on tumors before and after treatment with ipilimumab. RESULTS/ANTICIPATED RESULTS: Patients with evidence of clinical benefit (CB), as defined by having achieved partial response or stable disease, were compared with nonresponders (NR). All patients had an increase in IFN-γ, IL-2, and IL-10 secretion by CD4+ T-cells during ipilimumab therapy. NR had a statistically higher increase in all 3 cytokines. Mean IL-10 secretion was 22.3-fold higher compared with patients with CB (p value 0.0458; 95% CI=0.6676–43.89). Mean IFN-γ secretion was 12.4-fold higher from baseline levels in NR compared with CB (p value 0.046; 95% CI=0.3589–24.35). Mean IL-2 secretion was 6.9-fold higher in NR compared with CB (p value 0.032; 95% CI=0.9688–12.75). There were no statistically significant differences seen in the secretion of IL-4, IL-6, IL-17, or TNF-α. Multiplex immunofluorescence for immune profiling of 20 pre and post treatment tumor biopsies is ongoing. We expect to see distinct intratumoral lymphocyte compartment changes which correlate with clinical response and the above described differential cytokine profiles. Specifically, we anticipate CB patients will have increased intratumoral effector T-cells and decreased regulatory T-cells when compared with their NR counterparts. DISCUSSION/SIGNIFICANCE OF IMPACT: Cytokine expression profiles of peripheral blood CD4+ T-cells have not been previously correlated with patient response in patients undergoing treatment with ipilimumab. We describe distinct secretion profiles for IFN-γ, IL-2, and IL-10 for CB Versus NR patients. NR had a statistically higher increase in IL-10, an inhibitory cytokine which typically indicates upregulation of regulatory T-cells and consequent immune escape. Increased secretion of IL-2 and IFN-γ suggests skewing towards a Th1 type, anti-tumor effector T-cell response; these cytokines increased with ipilimumab treatment in both patient groups. However, the mean increase was several fold higher in NR. Recent evidence suggests loss of the interferon gamma pathway in tumor cells confers resistance to anti-CTLA4 therapy. Chronic IFN-γ secretion is associated with an exhausted T-cell phenotype and impaired tumor rejection. Therefore, higher increases in IFN-γ secretion by CD4+ T-cells in NR suggest impaired IFN-γ dependent tumor rejection in these patients. Our findings suggest IFN-γ, IL-2, and IL-10 cytokine expression profiles can be useful as biomarkers for response to ipilimumab treatment.