Phase I study of ribociclib and everolimus in children with newly diagnosed DIPG and high-grade glioma: A CONNECT pediatric neuro-oncology consortium report.

Background: Genomic aberrations in the cell cycle and PI3K/Akt/mTOR pathways have been reported in diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG). Dual inhibition of CDK4/6 and mTOR has biologic rationale and minimal overlapping toxicities. This study determined the recommended phase 2 dose (RP2D) of ribociclib and everolimus following radiotherapy in children with DIPG and HGG. Methods: Patients were enrolled according to a Rolling-6 design and received ribociclib and everolimus once daily for 21 and 28 days, respectively. All patients with HGG and biopsied DIPG were screened for retinoblastoma protein presence by immunohistochemistry. Pharmacokinetics were analyzed. Results: Nineteen patients enrolled (median age: 8 years [range: 2-18]). Three patients enrolled at each dose level 1 and 2 without dose-limiting toxicities (DLT). Thirteen patients were enrolled at dose level 3, with one patient experiencing a DLT (grade 3 infection). One patient came off therapy before cycle 9 due to cardiac toxicity. The most common grade 3/4 toxicities were neutropenia (33%), leucopenia (17%), and lymphopenia (11%). Steady-state everolimus exposures in combination were 1.9 ± 0.9-fold higher than single-agent administration. Median overall survival for 15 patients with DIPG was 13.9 months; median event-free survival for four patients with HGG was 10.5 months. Two longer survivors had tumor molecular profiling identifying CDKN2A/B deletion and CDK4 overexpression. Conclusion: The combination of ribociclib and everolimus following radiotherapy in children with newly diagnosed DIPG and HGG was well tolerated, with a RP2D of ribociclib 170 mg/m2 and everolimus 1.5 mg/m2. Results will inform a molecularly guided phase II study underway to evaluate efficacy.

Volumetric endpoints in diffuse intrinsic pontine glioma: comparison to cross-sectional measures and outcome correlations in the International DIPG/DMG Registry.

BACKGROUND: Cross-sectional tumor measures are traditional clinical trial endpoints; however volumetric measures may better assess tumor growth. We determined the correlation and compared the prognostic impact of cross-sectional and volumetric measures of progressive disease (PD) among patients with DIPG. METHODS: Imaging and clinical data were abstracted from the International DIPG Registry. Tumor volume and cross-sectional product (CP) were measured with mint Lesion™ software using manual contouring. Correlation between CP and volume (segmented and mathematical [ellipsoid] model) thresholds of PD were assessed by linear regression. Landmark analyses determined differences in survival (via log-rank) between patients classified as PD versus non-PD by CP and volumetric measurements at 1, 3, 5, 7, and 9 months postradiotherapy (RT). Hazard ratios (HR) for survival after these time points were calculated by Cox regression. RESULTS: A total of 312 MRIs (46 patients) were analyzed. Comparing change from the previous smallest measure, CP increase of 25% (PD) correlated with a segmented volume increase of 30% (R2 = 0.710), rather than 40% (spherical model extrapolation). CP-determined PD predicted survival at 1 month post-RT (HR = 2.77), but not other time points. Segmented volumetric-determined PD (40% threshold) predicted survival at all imaging timepoints (HRs = 2.57, 2.62, 3.35, 2.71, 16.29), and 30% volumetric PD threshold predicted survival at 1, 3, 5, and 9 month timepoints (HRs = 2.57, 2.62, 4.65, 5.54). Compared to ellipsoid volume, segmented volume demonstrated superior survival associations. CONCLUSIONS: Segmented volumetric assessments of PD correlated better with survival than CP or ellipsoid volume at most time points. Semiautomated tumor volume likely represents a more accurate, prognostically-relevant measure of disease burden in DIPG.

Overcoming barriers to establishing autopsy procurement programs in pediatric patients with central nervous system tumors: a call to develop regional centers.

BACKGROUND: While autopsy-repository programs with a variety of pediatric central nervous system (CNS) tumor types are a critical resource for preclinical neuro-oncology research, few exist and there is no published guidance on how to develop one. The goal of this prospective Pediatric Brain Tumor Repository (PBTR) study was to develop such a program at Cincinnati Children's Hospital Medical Center (CCHMC) and then publish the quantitative and experiential data as a guide to support the development of similar programs. METHODS: Protocols and infrastructure were established-to educate oncologists and families, establish eligibility, obtain consent, address pre- and post-autopsy logistics (e.g., patient and tissue transportation), process and authenticate tissue samples, and collect and analyze data. RESULTS: Of the 129 pediatric CNS tumor patients at CCHMC who died between 2013 and 2018, 109 were eligible for our study. Of these, 74% (81 of 109) were approached for PBTR donation, and 68% (55 of 81) consented. In the final year of the study, approach and consent rates were 93% and 85%, respectively. Median time from death to autopsy (postmortem interval, PMI) was 10 h (range, 1.5-30). In the outpatient setting, PMI increased with distance (from the hospice/home where the patient died to CCHMC). In all patients, PMI appeared to be lower, when consent was obtained more than 24 h before death. CONCLUSIONS: Procurement of autopsy specimens need not be a barrier in neuro-oncology research. Regional centers, strict timing-of-consent, patient education, and dedicated staff are all needed to minimize PMI and, thereby, increase the value of the procured tissue for an array of basic and translational research applications.

Trametinib-associated Hyponatremia in a Child With Low-grade Glioma is Not Seen Following Treatment With Alternative MEK Inhibitor.

Molecularly targeted therapy with MEK inhibitors has been increasingly incorporated into the treatment of pediatric low-grade gliomas, but this promising therapy is associated with distinctive and specific toxicities. Understanding life-threatening MEK inhibitor toxicities and their management is critical to MEK inhibitor safety, especially among young children. This report describes severe hyponatremia associated with trametinib in an infant with progressive low-grade glioma without underlying endocrine dysfunction, which recurred despite significant dose reduction. Therapy with an alternative MEK inhibitor, binimetinib, provided excellent tumor response without hyponatremia, suggesting that some toxicities may be avoided by changing MEK inhibitor agents within the same class.

Characterizing temporal genomic heterogeneity in pediatric low-grade gliomas.

Recent discoveries have provided valuable insight into the genomic landscape of pediatric low-grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs' genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and/or targeted sequencing were performed on paired tumor samples from primary diagnostic and subsequent surgeries. Ninety-four tumor samples from 45 patients (41 with two specimens, four with three specimens) from three institutions underwent testing. Conservation of BRAF fusion, BRAFV600E mutation, and FGFR1 rearrangement status was observed in 100%, 98%, and 96% of paired specimens, respectively. No loss or gain of IDH1 mutations or NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. Changes in CDKN2A deletion status at recurrence occurred in 11 patients (42%), with acquisition of hemizygous CDKN2A deletion in seven and loss in four. Shorter time to progression and shorter time to subsequent surgery were observed among patients with acquired CDKN2A deletions compared to patients without acquisition of this alteration [median time to progression: 5.5 versus 16.0 months (p = 0.048); median time to next surgery: 17.0 months versus 29.0 months (p = 0.031)]. Most targetable genetic aberrations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or irradiation. However, changes in CDKN2A deletion status over time were demonstrated. Acquisition of CDKN2A deletion may define a higher risk subgroup of pediatric LGGs with a poorer prognosis. Given the potential for targeted therapies for tumors harboring CDKN2A deletions, biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.

Visual field outcomes in children treated for neurofibromatosis type 1-associated optic pathway gliomas: a multicenter retrospective study.

BACKGROUND: Optic pathway gliomas associated with neurofibromatosis type 1 (NF1-OPGs) may adversely affect visual acuity, but data regarding visual field (VF) outcomes after treatment in children are limited. The purpose of this study was to investigate the effects of NF1-OPGs on VF function in a large cohort of children after treatment with chemotherapy. METHODS: We performed a retrospective, international, multicenter study of VF outcomes in patients treated with chemotherapy for NF1-OPGs. RESULTS: A total of 25 participants underwent VF testing using formal perimetric techniques. At the end of treatment, 19 participants (76%) had persistent VF deficits. Formal VF testing was available for 16 participants (64%) at initiation and completion of treatment. Of the 16 children who underwent VF testing at initiation and completion of treatment, 7 (44%) showed stability of VF changes, 3 (19%) showed improvement of VF function, and 6 (38%) had worsening of VFs. Improvement or worsening of VF outcome did not always correlate with visual acuity outcome. Posterior tumor location involving the optic tracts and radiations was associated with more frequent and more profound VF defects. CONCLUSIONS: In our study cohort, children undergoing initial chemotherapy for NF1-OPGs had a high prevalence of VF loss, which could be independent of visual acuity loss. A larger, prospective study is necessary to fully determine the prevalence of VF loss and the effects of chemotherapy on VF outcomes in children with NF1-OPGs.

A phase I/II study of ribociclib following radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG).

PURPOSE: Cyclin-dependent kinase-retinoblastoma (CDK-RB) pathway is dysregulated in some diffuse intrinsic pontine gliomas (DIPG). We evaluated safety, feasibility, and early efficacy of the CDK4/6-inhibitor ribociclib, administered following radiotherapy in newly-diagnosed DIPG patients. METHODS: Following radiotherapy, eligible patients received ribociclib in 28-day cycles (350 mg/m2; 21 days on/7 days off). Feasibility endpoints included tolerability for at least 6 courses, and a less than 2-week delay in restarting therapy after 1 dose reduction. Early efficacy was measured by 1-year and median overall survival (OS). Patient/parent-by-proxy reported outcomes measurement information system (PROMIS) assessments were completed prospectively. RESULTS: The study included 10 evaluable patients, 9 DIPG and 1 diffuse midline glioma (DMG)-all 3.7 to 19.8 years of age. The median number of courses was 8 (range 3-14). Three patients required dose reduction for grade-4 neutropenia, and 1 discontinued therapy for hematological toxicity following course 4. The most common grade-3/4 toxicity was myelosuppression. After 2 courses, MRI evaluations in 4 patients revealed increased necrotic volume, associated with new neurological symptoms in 3 patients. The 1-year and median OS for DIPG was 89% and 16.1 months (range 10-30), respectively; the DMG patient died at 6 months post-diagnosis. Five patients donated brain tissue and tumor; 3 were RB+ . CONCLUSIONS: Ribociclib administered following radiotherapy is feasible in DIPG and DMG. Increased tumor necrosis may represent a treatment effect. These data warrant further prospective volumetric analyses of tumors with necrosis. Feasibility and stabilization findings support further investigation of ribociclib in combination therapies. TRIAL REGISTRATION: NCT02607124.

A Phase I and Pharmacokinetic Study of Oral Dabrafenib in Children and Adolescent Patients with Recurrent or Refractory BRAF V600 Mutation-Positive Solid Tumors.

PURPOSE: The 2-part, phase I/IIa, open-label study (NCT01677741) sought to determine the safety, tolerability, pharmacokinetics, and preliminary activity of dabrafenib in pediatric patients with advanced BRAF V600-mutated cancers. PATIENTS AND METHODS: This phase I dose-finding part treated patients ages 1 to <18 years with BRAF V600 mutation-positive tumors with oral dabrafenib 3 to 5.25 mg/kg/day to determine the RP2D based on safety and drug exposure target. RESULTS: Between May 2013 and November 2014, 27 patients [12 male; median age, 9 years (range, 1-17 years)] with BRAF V600-mutant solid tumors recurrent/refractory to treatment (low- or high-grade glioma, Langerhans cell histiocytosis, neuroblastoma, or thyroid cancer) were enrolled. The median treatment duration was 75.6 weeks (range, 5.6-148.7 weeks), with 63% treated for >52 weeks and 52% undergoing treatment at data cutoff date. The most common grade 3/4 adverse events suspected to be related to study drug were maculopapular rash and arthralgia (2 patients each). No dose-limiting toxicities were observed. Pharmacokinetic analyses showed a dose-dependent increase in AUC0-12 and achievement of adult exposure levels at the recommended phase II doses of 5.25 mg/kg/day (age <12 years) and 4.5 mg/kg/day (age ≥12 years) divided into 2 equal doses daily, not exceeding 300 mg daily. CONCLUSIONS: In this first clinical trial in pediatric patients with pretreated BRAF V600-mutant tumors, dabrafenib was well tolerated while achieving target exposure levels; the average treatment duration was >1 year with many patients still on treatment. The phase II component is also closed and will be reported separately.

Malignant peripheral nerve sheath tumor: Transformation in a patient with neurofibromatosis type 2.

Malignant peripheral nerve sheath tumor (MPNST) is a rare soft-tissue sarcoma with an unfavorable prognosis and limited therapeutic options. MPNSTs can be sporadic, but are often associated with neurofibromatosis (NF) 1 and usually arise from preexisting neurofibromas. MPNSTs in patients with NF2 have been reported in only exceedingly rare cases, and the mechanisms underlying transformation into an MPNST have not been fully elucidated. Here, we describe the clinicopathological and genomic features of a peripheral nerve sheath tumor (PNST), with a primary diagnosis of a neurofibroma, as it transforms into a high-grade MPNST in the context of NF2.

Pediatric intramedullary spinal cord tumor outcomes using the WeeFIM scale.

PURPOSE: The Functional Independence Measure for children (WeeFIM) is a user-friendly functional outcomes tool that has been validated across other traditional functional scales. Historically, the significant neurologic and functional deficits of intramedullary spinal cord tumors (IMSCTs) have been monitored by coarse or overbearing functional outcomes tools that make it difficult to measure the slow improvement/decline seen in these patients. This study is the first to report WeeFIM outcomes on a series of IMSCTs with emphasis on an aggressive surgical strategy. METHODS: A retrospective review from 2005 to 2014 was performed for nine patients who underwent resective surgery for intramedullary spinal cord tumors with intraoperative ultrasound and neurophysiologic monitoring. WeeFIM scales were assessed at admission and discharge to evaluate changes in severity of disability and need for assistance. RESULTS: At the time of this submission, 7/9 patients are alive. The mean WeeFIM improvement was 27 points (8-50 points) with a mean WeeFIM efficiency of 2.0 points/day. CONCLUSIONS: The WeeFIM scale is an appropriate and useful scale for measuring postoperative improvements in patients with IMSCTs undergoing aggressive resective surgery. Attention to intraoperative spinal cord monitoring and prevention of spinal column instability may prevent morbidity related to surgery, and functional outcomes do not appear to be compromised by an aggressive surgical approach.

Characterizing temporal genomic heterogeneity in pediatric high-grade gliomas.

Pediatric high-grade gliomas (pHGGs) are aggressive neoplasms representing approximately 20% of brain tumors in children. Current therapies offer limited disease control, and patients have a poor prognosis. Empiric use of targeted therapy, especially at progression, is increasingly practiced despite a paucity of data regarding temporal and therapy-driven genomic evolution in pHGGs. To study the genetic landscape of pHGGs at recurrence, we performed whole exome and methylation analyses on matched primary and recurrent pHGGs from 16 patients. Tumor mutational profiles identified three distinct subgroups. Group 1 (n = 7) harbored known hotspot mutations in Histone 3 (H3) (K27M or G34V) or IDH1 (H3/IDH1 mutants) and co-occurring TP53 or ACVR1 mutations in tumor pairs across the disease course. Group 2 (n = 7), H3/IDH1 wildtype tumor pairs, harbored novel mutations in chromatin modifiers (ZMYND11, EP300 n = 2), all associated with TP53 alterations, or had BRAF V600E mutations (n = 2) conserved across tumor pairs. Group 3 included 2 tumors with NF1 germline mutations. Pairs from primary and relapsed pHGG samples clustered within the same DNA methylation subgroup. ATRX mutations were clonal and retained in H3G34V and H3/IDH1 wildtype tumors, while different genetic alterations in this gene were observed at diagnosis and recurrence in IDH1 mutant tumors. Mutations in putative drug targets (EGFR, ERBB2, PDGFRA, PI3K) were not always shared between primary and recurrence samples, indicating evolution during progression. Our findings indicate that specific key driver mutations in pHGGs are conserved at recurrence and are prime targets for therapeutic development and clinical trials (e.g. H3 post-translational modifications, IDH1, BRAF V600E). Other actionable mutations are acquired or lost, indicating that re-biopsy at recurrence will provide better guidance for effective targeted therapy of pHGGs.

A comparison of safety and efficacy of cytotoxic versus molecularly targeted drugs in pediatric phase I solid tumor oncology trials.

BACKGROUND: Prior reviews of phase I pediatric oncology trials involving primarily cytotoxic agents have reported objective response rates (ORRs) and toxic death rates of 7.9-9.6% and 0.5%, respectively. These data may not reflect safety and efficacy in phase I trials of molecularly targeted (targeted) drugs. METHODS: A systematic review of pediatric phase I solid tumor trials published in 1990-2013 was performed. The published reports were evaluated for patient characteristics, toxicity information, and response numbers. RESULTS: A total of 143 phase I pediatric clinical trials enrolling 3,896 children involving 53 targeted and 48 cytotoxic drugs were identified. A meta-analysis demonstrated that the ORR is 2.1-fold higher with cytotoxic drugs (0.066 vs. 0.031 per subject; P = 0.007). By contrast, the pooled estimate of the stable disease rate (SDR) is similar for cytotoxic and targeted drugs (0.2 vs. 0.23 per subject; P = 0.27).  The pooled estimate of the dose-limiting toxicity rate is 1.8-fold larger with cytotoxic drugs (0.24 vs. 0.13 per subject; P = 0.0003). The hematologic grade 3-4 (G3/4) toxicity rate is 3.6-fold larger with cytotoxic drugs (0.43 vs. 0.12 per treatment course; P = 0.0001); however, the nonhematologic G3/4 toxicities and toxic deaths occur at similar rates for cytotoxic and targeted drugs. CONCLUSIONS: In phase I pediatric solid tumor trials, ORRs were significantly higher for cytotoxic versus targeted agents. SDRs were similar in targeted and cytotoxic drug trials. Patients treated with cytotoxic agents were more likely to experience hematologic G3/4 toxicities than those patients receiving targeted drugs.

A molecular biology and phase II study of imetelstat (GRN163L) in children with recurrent or refractory central nervous system malignancies: a pediatric brain tumor consortium study.

Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted an investigator-sponsored molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-h intravenous infusion at 285 mg/m(2), 12-24 h before surgery. Telomerase activity was evaluated in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q21-days) at 285 mg/m(2). Imetelstat pharmacokinetic and pharmacodynamic studies were performed. Of two evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95 % compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5 %), lymphopenia (17.5 %), neutropenia (12.5 %), ALT (7.5 %) and AST (5 %) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.

A pilot study of bevacizumab-based therapy in patients with newly diagnosed high-grade gliomas and diffuse intrinsic pontine gliomas.

Although bevacizumab has not proven effective in adults with newly diagnosed high-grade gliomas (HGG), feasibility in newly diagnosed children with diffuse intrinsic pontine gliomas (DIPG) or HGG has not been reported in a prospective study. In a safety and feasibility study, children and young adults with newly diagnosed HGG received radiotherapy (RT) with bevacizumab (10 mg/kg: days 22, 36) and temozolomide (75-90 mg/m(2)/day for 42 days) followed by bevacizumab (10 mg/kg, days 1, 15), irinotecan (125 mg/m(2), days 1, 15) and temozolomide (150 mg/m(2)/day days 1-5). DIPG patients did not receive temozolomide. Telomerase activity, quality of life (QOL), and functional outcomes were assessed. Among 27 eligible patients (15 DIPG, 12 HGG), median age 10 years (range 3-29 years), 6 discontinued therapy for toxicity: 2 during RT (grade 4 thrombocytopenia, grade 3 hepatotoxicity) and 4 during maintenance therapy (grade 3: thrombosis, hypertension, skin ulceration, and wound dehiscence). Commonest ≥grade 3 toxicities included lymphopenia, neutropenia and leukopenia. Grade 3 hypertension occurred in 2 patients. No intracranial hemorrhages occurred. For DIPG patients, median overall survival (OS) was 10.4 months. For HGG patients, 3-year progression free survival and OS were 33 % (SE ± 14 %) and 50 % (SE ± 14 %), respectively. All 3 tested tumor samples, demonstrated histone H3.3K27M (n = 2 DIPG) or G34R (n = 1 HGG) mutations. QOL scores improved over the course of therapy. A bevacizumab-based regimen is feasible and tolerable in newly diagnosed children and young adults with HGG and DIPG.

The Use of Magnetic Resonance Imaging Screening for Optic Pathway Gliomas in Children with Neurofibromatosis Type 1.

OBJECTIVE: To evaluate the utility of screening brain/orbital magnetic resonance imaging (MRI) in a large population of children with neurofibromatosis type 1 (NF1) over a 20-year period. STUDY DESIGN: A retrospective analysis of clinical and imaging data from children with NF1 seen at a single center between 1990 and 2010 was performed. RESULTS: During the 20-year study period, 826 individuals with NF1 (402 females, 424 males) ages 1-9 years were screened for optic pathway gliomas (OPGs) using brain/orbital MRI; 18% were identified with OPGs with a median age at detection of 3 years. Fifteen percent of patients with OPGs had radiologic or clinical progression requiring therapy. Children with chiasmatic and postchiasmatic tumors were more likely to require therapy compared with patients with prechiasmatic OPGs (P < .0001). Patients with visual deficits at the time of diagnosis were more likely to experience visual decline despite therapy when compared with patients treated based on radiologic progression (P < .012). CONCLUSIONS: Our findings confirm that chiasmatic and postchiasmatic OPG in children with NF1 have the highest risk for progression and vision loss. Early identification of OPG by screening MRI prior to the development of vision loss may lead to improved visual outcomes. Children with negative brain and orbital MRI screening at age 15 months or later did not develop symptomatic OPGs.

Nocardia farcinica Meningitis Masquerading as Central Nervous System Metastasis in a Child With Cerebellar Pilocytic Astrocytoma.

Juvenile pilocytic astrocytoma, the most common pediatric central nervous system (CNS) neoplasm, characteristically displays an indolent growth pattern and rarely demonstrates metastatic dissemination. Reports of infections mimicking CNS metastatic disease are also rare and can impact treatment. We report the youngest known case of a child with a CNS Nocardia farcinica infection who had a known cerebellar pilocytic astrocytoma, review other infections that may masquerade as CNS neoplasms, and discuss N. farcinica CNS infections.

Pediatric tectal plate gliomas: a review of clinical outcomes, endocrinopathies, and neuropsychological sequelae.

Pediatric tectal plate gliomas are indolent slow-growing gliomas that often present with increased intracranial pressure or incidentally on routine brain imaging. We investigated clinical outcomes, endocrinopathies, and neuropsychological sequelae associated with tectal plate gliomas. Twenty-six patients with tectal plate glioma were identified in a 20-year retrospective review. Clinical outcomes, treatments, endocrine function, neuropsychological testing outcomes and radiographic imaging were reviewed for possible signs correlating with tumor progression. Among 26 patients, 19 presented with signs or symptoms of increased intracranial pressure (73 %) versus an incidental finding in 7 (27 %). Median follow-up was 46 months (range 8-143 months). Six of 26 (23 %) experienced progressive disease after diagnosis. Five of 26 (19 %) required more than one surgical procedure due to failure of initial endoscopic third ventriculostomy. Seven of 26 had history of endocrine dysfunction, of which, five presented with endocrine dysfunction (precocious puberty or short stature), 1 developed menstrual irregularities after surgical intervention and 1 had preexisting pan hypopituitarism. Of 12 patients with available neuropsychological testing, eleven had at least one indicator of executive functioning in the low-average to impaired range. While tectal plate gliomas have been considered indolent tumors that are rarely progressive, 23 % of patients in our cohort experienced disease progression and required further therapy. Neurocognitive deficits may occur, while endocrine deficiency is uncommon. Regular multidisciplinary oncology follow-up, routine monitoring with MRI and formal neurocognitive evaluation are imperative to provide early recognition of disease progression or recurrent hydrocephalus and to improve school functioning in this population.

A pediatric phase 1 trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors: a Children's Oncology Group phase 1 consortium study.

PURPOSE: We conducted a pediatric phase I study to estimate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic properties of vorinostat, a histone deacetylase (HDAC) inhibitor, when given in combination with temozolomide in children with refractory or recurrent CNS malignancies. PATIENTS AND METHODS: Vorinostat, followed by temozolomide approximately 1 hour later, was orally administered, once daily, for 5 consecutive days every 28 days at three dose levels using the rolling six design. Studies of histone accumulation in peripheral blood mononuclear cells were performed on Day 1 at 0, 6, and 24 hours after vorinostat dosing. Vorinostat pharmacokinetics (PK) and serum MGMT promoter status were also assessed. RESULTS: Nineteen eligible patients were enrolled and 18 patients were evaluable for toxicity. There were no DLTs observed at dose level 1 or 2. DLTs occurred in four patients at dose level 3: thrombocytopenia (4), neutropenia (3), and leucopenia (1). Non-dose limiting grade 3 or 4 toxicities related to protocol therapy were also hematologic and included neutropenia, lymphopenia, thrombocytopenia, anemia, and leucopenia. Three patients exhibited stable disease and one patient had a partial response. There was no clear relationship between vorinostat dosage and drug exposure over the dose range studied. Accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat. CONCLUSION: Five-day cycles of vorinostat in combination with temozolomide are well tolerated in children with recurrent CNS malignancies with myelosuppression as the DLT. The recommended phase II combination doses are vorinostat, 300 mg/m(2) /day and temozolomide, 150 mg/m(2) /day.

Pharmacotherapeutic management of pediatric gliomas : current and upcoming strategies.

Primary glial brain tumors account for the majority of primary brain tumors in children. They are classified as low-grade gliomas (LGG) or high-grade gliomas (HGG), based on specific pathologic characteristics of the tumor, resulting in disparate clinical prognoses. Surgery is a mainstay of treatment for HGG, although it is not curative, and adjuvant therapy is required. Temozolomide, an oral imidazotetrazine prodrug, while considered standard of care for adult HGG, has not shown the same degree of benefit in the treatment of pediatric HGG. There are significant biologic differences that exist between adult and pediatric HGG, and targets specifically aimed at the biology in the pediatric population are required. Novel and specific therapies currently being investigated for pediatric HGG include small molecule inhibitors of epidermal growth factor receptor, platelet-derived growth factor receptor, histone deacetylase, the RAS/AKT pathway, telomerase, integrin, insulin-like growth factor receptor, and γ-secretase. Surgery is also the mainstay for LGG. There are defined front-line, multiagent chemotherapy regimens, but there are few proven second-line chemotherapy options for refractory patients. Approaches such as the inhibition of the mammalian target of rapamycin pathway, inhibition of MEK1 and 2, as well as BRAF, are discussed. Further research is required to understand the biology of pediatric gliomas as well as the use of molecularly targeted agents, especially in patients with surgically unresectable tumors.