Magnetic Resonance Spectroscopy Metabolites as Biomarkers of Disease Status in Pediatric Diffuse Intrinsic Pontine Gliomas (DIPG) Treated with Glioma-Associated Antigen Peptide Vaccines.

PURPOSE: Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive tumors with no currently available curative therapy. This study evaluated whether measurements of in vivo cell metabolites using magnetic resonance spectroscopy (MRS) may serve as biomarkers of response to therapy, including progression. METHODS: Single-voxel MR spectra were serially acquired in two cohorts of patients with DIPG treated with radiation therapy (RT) with or without concurrent chemotherapy and prior to progression: 14 participants were enrolled in a clinical trial of adjuvant glioma-associated antigen peptide vaccines and 32 patients were enrolled who did not receive adjuvant vaccine therapy. Spearman correlations measured overall survival associations with absolute metabolite concentrations of myo-inositol (mI), creatine (Cr), and n-acetyl-aspartate (NAA) and their ratios relative to choline (Cho) during three specified time periods following completion of RT. Linear mixed-effects regression models evaluated the longitudinal associations between metabolite ratios and time from death (terminal decline). RESULTS: Overall survival was not associated with metabolite ratios obtained shortly after RT (1.9-3.8 months post-diagnosis) in either cohort. In the vaccine cohort, an elevated mI/Cho ratio after 2-3 doses (3.9-5.2 months post-diagnosis) was associated with longer survival (rho = 0.92, 95% CI 0.67-0.98). Scans performed up to 6 months before death showed a terminal decline in the mI/Cho ratio, with an average of 0.37 ratio/month in vaccine patients (95% CI 0.11-0.63) and 0.26 (0.04-0.48) in the non-vaccine cohort. CONCLUSION: Higher mI/Cho ratios following RT, consistent with less proliferate tumors and decreased cell turnover, were associated with longer survival, suggesting that this ratio can serve as a biomarker of prognosis following RT. This finding was seen in both cohorts, although the association with OS was detected earlier in the vaccine cohort. Increased mI/Cho (possibly reflecting immune-effector cell influx into the tumor as a mechanism of tumor response) requires further study.

Quantitative Sodium (23Na) MRI in Pediatric Gliomas: Initial Experience.

Background: 23Na MRI correlates with tumor proliferation, and studies in pediatric patients are lacking. The purpose of the study: (1) to compare total sodium concentration (TSC) between pediatric glioma and non-neoplastic brain tissue using 23Na MRI; (2) compare tissue conspicuity of bound sodium concentration (BSC) using 23Na MRI dual echo relative to TSC imaging. Methods: TSC was measured in: (1) non-neoplastic brain tissues and (2) three types of manually segmented gliomas (diffuse intrinsic brainstem glioma (DIPG), recurrent supratentorial low-grade glioma (LGG), and high-grade glioma (HGG)). In a subset of patients, serial changes in both TSC and BSC (dual echo 23Na MRI) were assessed. Results: Twenty-six pediatric patients with gliomas (median age of 12.0 years, range 4.9−23.3 years) were scanned with 23Na MRI. DIPG treated with RT demonstrated higher TSC values than the uninvolved infratentorial tissues (p < 0.001). Recurrent supratentorial LGG and HGG exhibited higher TSC values than the uninvolved white matter (WM) and gray matter (GM) (p < 0.002 for LGG, and p < 0.02 for HGG). The dual echo 23Na MRI suppressed the sodium signal within both CSF and necrotic foci. Conclusion: Quantitative 23Na MRI of pediatric gliomas demonstrates a range of values that are higher than non-neoplastic tissues. Dual echo 23Na MRI of BCS improves tissue conspicuity relative to TSC imaging.

Phase II study of peginterferon alpha-2b for patients with unresectable or recurrent craniopharyngiomas: a Pediatric Brain Tumor Consortium report.

BACKGROUND: Craniopharyngiomas account for approximately 1.2-4% of all CNS tumors. They are typically treated with a combination of surgical resection and focal radiotherapy. Unfortunately, treatment can lead to permanent deleterious effects on behavior, learning, and endocrine function. METHODS: The Pediatric Brain Tumor Consortium performed a multicenter phase 2 study in children and young adults with unresectable or recurrent craniopharyngioma (PBTC-039). Between December 2013 and November 2017, nineteen patients (median age at enrollment, 13.1 y; range, 2-25 y) were enrolled in one of 2 strata: patients previously treated with surgery alone (stratum 1) or who received radiation (stratum 2). RESULTS: Eighteen eligible patients (8 male, 10 female) were treated with weekly subcutaneous pegylated interferon alpha-2b for up to 18 courses (108 wk). Therapy was well tolerated with no grade 4 or 5 toxicities. 2 of the 7 eligible patients (28.6%) in stratum 1 had a partial response, but only one response was sustained for more than 3 months. None of the 11 stratum 2 patients had an objective radiographic response, although median progression-free survival was 19.5 months. CONCLUSIONS: Pegylated interferon alpha-2b treatment, in lieu of or following radiotherapy, was well tolerated in children and young adults with recurrent craniopharyngiomas. Although objective responses were limited, progression-free survival results are encouraging, warranting further studies.

Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial.

BACKGROUND: Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients. METHODS: The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3-21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAFV600E [Val600Glu] mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101. FINDINGS: Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14-51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No treatment-realted deaths were reported. INTERPRETATION: Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1. FUNDING: National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.

A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study.

BACKGROUND: Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG. METHODS: Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course. BRAF aberrations in tumor tissue were determined by real-time polymerase chain reaction and fluorescence in situ hybridization. RESULTS: Thirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2-3 rash (n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, the median (range) area under the curve (AUC0-∞) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng × h/mL) and 6.5 L × h-1 × m-2 (3.4 to 14.0 L × h-1 × m-2), respectively. Thirteen of 19 tumors had BRAF abnormalities. Among the 5 (20%) of 25 subjects with sustained partial responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. Subjects received a median of 13 cycles (range: 1-26). Fourteen (37%) completed all protocol treatment (26 cycles [n = 13], 13 cycles [n = 1]) with at least stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 9.8%. CONCLUSION: Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.

Neuroimaging of Peptide-based Vaccine Therapy in Pediatric Brain Tumors: Initial Experience.

The potential benefits of peptide-based immunotherapy for pediatric brain tumors are under investigation. Treatment-related heterogeneity has resulted in radiographic challenges, including pseudoprogression. Conventional MR imaging has limitations in assessment of different forms of treatment-related heterogeneity, particularly regarding distinguishing true tumor progression from efficacious treatment responses. Advanced neuroimaging techniques, including diffusion magnetic resonance (MR), perfusion MR, and MR spectroscopy, may add value in the assessment of treatment-related heterogeneity. Observations suggest that recent delineation of specific response criteria for immunotherapy of adult brain tumors is likely relevant to the pediatric population and further validation in multicenter pediatric brain tumor peptide-based vaccine studies is warranted.

Phase II trial of pegylated interferon alfa-2b in young patients with neurofibromatosis type 1 and unresectable plexiform neurofibromas.

Background: There is no proven medical therapy for plexiform neurofibromas (PNs). We undertook a phase II trial of pegylated interferon (PI) to evaluate response and time to progression (TTP). Methods: PI was administered as a subcutaneous injection to patients with neurofibromatosis type 1‒related PN, stratified by the presence of symptoms (asymptomatic: stratum 1, symptomatic: stratum 2) or documented imaging progression (stratum 3). Patients in strata 1 and 2 received PI for up to one year if stable, 2 years for those with clinical (stratum 2) or imaging response (≥20% decrease in volume). Patients on stratum 3 continued PI until progression. PI was considered active in stratum 3 if TTP doubled compared with the placebo arm of a previous randomized trial using tipifarnib. Results: Enrolled were 82 evaluable patients (median age 10 y; range 1.6 to 21.4). Fatigue and/or worsening of behavioral issues were the most common toxicities requiring dose modification. Across all strata, imaging responses were seen in 4 patients (5%). Three of 26 symptomatic patients on stratum 2 met the criteria for clinical response without corresponding imaging changes. In stratum 3, median TTP was 29.4 months versus 11.8 for the placebo arm of the previous trial (P=.031). The slope of tumor growth on PI slowed significantly compared with the slope before starting PI (P=.044). Conclusions: In patients with active PN, PI results in more than doubling of the TTP compared with placebo. Imaging changes in symptomatic patients were not associated with changes in clinical status.

Antigen-specific immunoreactivity and clinical outcome following vaccination with glioma-associated antigen peptides in children with recurrent high-grade gliomas: results of a pilot study.

Recurrent high-grade gliomas (HGGs) of childhood have an exceedingly poor prognosis with current therapies. Accordingly, new treatment approaches are needed. We initiated a pilot trial of vaccinations with peptide epitopes derived from glioma-associated antigens (GAAs) overexpressed in these tumors in HLA-A2+ children with recurrent HGG that had progressed after prior treatments. Peptide epitopes for three GAAs (EphA2, IL13Rα2, survivin), emulsified in Montanide-ISA-51, were administered subcutaneously adjacent to intramuscular injections of poly-ICLC every 3 weeks for 8 courses, followed by booster vaccines every 6 weeks. Primary endpoints were safety and T-cell responses against the GAA epitopes, assessed by enzyme-linked immunosorbent spot (ELISPOT) analysis. Treatment response was evaluated clinically and by magnetic resonance imaging. Twelve children were enrolled, 6 with glioblastoma, 5 with anaplastic astrocytoma, and one with malignant gliomatosis cerebri. No dose-limiting non-CNS toxicity was encountered. ELISPOT analysis, in ten children, showed GAA responses in 9: to IL13Rα2 in 4, EphA2 in 9, and survivin in 3. One child had presumed symptomatic pseudoprogression, discontinued vaccine therapy, and responded to subsequent treatment. One other child had a partial response that persisted throughout 2 years of vaccine therapy, and continues at >39 months. Median progression-free survival (PFS) from the start of vaccination was 4.1 months and median overall survival (OS) was 12.9 months. 6-month PFS and OS were 33 and 73 %, respectively. GAA peptide vaccination in children with recurrent malignant gliomas is generally well tolerated, and has preliminary evidence of immunological and modest clinical activity.

Single-agent erlotinib versus oral etoposide in patients with recurrent or refractory pediatric ependymoma: a randomized open-label study.

Overexpression of human epidermal growth factor receptor (HER/EGFR) is associated with various tumors, including ependymomas. To investigate whether EGFR inhibition was of benefit in pediatric patients with recurrent ependymoma, a multi-center, randomized, open-label, phase 2 study of oral erlotinib versus oral etoposide was undertaken. Twenty-five patients were randomized to receive erlotinib 85 mg/m(2) daily or etoposide 50 mg/m(2)/day for 21 consecutive days followed by a 7-day rest period. Courses were repeated every 28 days. In the erlotinib arm, no patient achieved a complete, partial, or minor response, and only 2 (15.4 %) patients showed stable disease as their best response. In the etoposide arm, 2 patients (16.7 %) demonstrated partial responses, 1 (8.3 %) patient demonstrated a minor response, and 2 (16.7 %) showed prolonged stable disease, for a prolonged disease control rate of 41.7 %. Three patients received at least nine cycles of etoposide (range 9-24 cycles) before discontinuing at the request of the physician and/or family. Four patients who failed etoposide in this study received erlotinib in a companion single arm study; none had a response. The futility criteria were met at the second interim analysis, and both studies were discontinued. Pharmacokinetics of erlotinib were similar to previous observations in pediatric patients. Overall, erlotinib was well tolerated and safety was consistent with its established profile in adults. The overall risk-benefit profile does not support the use of erlotinib in pediatric patients with recurrent ependymoma, whereas single-agent etoposide appears to have efficacy in a subset of patients.

Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: a report of the Children's Oncology Group ACNS0423 study.

BACKGROUND: The prognosis for children with malignant glioma is poor. This study was designed to determine whether lomustine and temozolomide following radiotherapy and concurrent temozolomide improves event-free survival (EFS) compared with historical controls with anaplastic astrocytoma (AA) or glioblastoma (GBM) and whether survival is influenced by the expression of O6-methylguanine-DNA-methyltransferase (MGMT). METHODS: Following maximal surgical resection, newly diagnosed children with nonmetastatic high-grade glioma underwent involved field radiotherapy with concurrent temozolomide. Adjuvant chemotherapy consisted of up to 6 cycles of lomustine 90 mg/m(2) on day 1 and temozolomide 160 mg/m(2)/day ×5 every 6 weeks. RESULTS: Among the 108 eligible patients with AA or GBM, 1-year EFS was 0.49 (95% CI, 0.39-0.58), similar to the original CCG-945-based design model. However, EFS and OS were significantly improved in ACNS0423 compared with the 86 AA or GBM participants treated with adjuvant temozolomide alone in the recent ACNS0126 study (1-sided log-rank P = .019 and .019, respectively). For example, 3-year EFS was 0.22 (95% CI, 0.14-0.30) in ACNS0423 compared with 0.11 (95% CI, 0.05-0.18) in ACNS0126. Stratifying the comparison by resection extent, the addition of lomustine resulted in significantly better EFS and OS in participants without gross-total resection (P = .019 and .00085 respectively). The difference in EFS and OS was most pronounced for participants with GBM (P = .059 and 0.051, respectively), and those with MGMT overexpression (P = .00036 and .00038, respectively). CONCLUSION: The addition of lomustine to temozolomide as adjuvant therapy in ACNS0423 was associated with significantly improved outcome compared with the preceding COG ACNS0126 HGG study in which participants received temozolomide alone.

Immune responses and outcome after vaccination with glioma-associated antigen peptides and poly-ICLC in a pilot study for pediatric recurrent low-grade gliomas.

BACKGROUND: Low-grade gliomas (LGGs) are the most common brain tumors of childhood. Although surgical resection is curative for well-circumscribed superficial lesions, tumors that are infiltrative or arise from deep structures are therapeutically challenging, and new treatment approaches are needed. Having identified a panel of glioma-associated antigens (GAAs) overexpressed in these tumors, we initiated a pilot trial of vaccinations with peptides for GAA epitopes in human leukocyte antigen-A2+ children with recurrent LGG that had progressed after at least 2 prior regimens. METHODS: Peptide epitopes for 3 GAAs (EphA2, IL-13Rα2, and survivin) were emulsified in Montanide-ISA-51 and administered subcutaneously adjacent to intramuscular injections of polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose every 3 weeks for 8 courses, followed by booster vaccines every 6 weeks. Primary endpoints were safety and T-lymphocyte responses against GAA epitopes. Treatment response was evaluated clinically and by MRI. RESULTS: Fourteen children were enrolled. Other than grade 3 urticaria in one child, no regimen-limiting toxicity was encountered. Vaccination induced immunoreactivity to at least one vaccine-targeted GAA in all 12 evaluable patients: to IL-13Rα2 in 3, EphA2 in 11, and survivin in 3. One child with a metastatic LGG had asymptomatic pseudoprogression noted 6 weeks after starting vaccination, followed by dramatic disease regression with >75% shrinkage of primary tumor and regression of metastatic disease, persisting >57 months. Three other children had sustained partial responses, lasting >10, >31, and >45 months, and one had a transient response. CONCLUSIONS: GAA peptide vaccination in children with recurrent LGGs is generally well tolerated, with preliminary evidence of immunological and clinical activity.

Outcome and prognostic factors for children with supratentorial primitive neuroectodermal tumors treated with carboplatin during radiotherapy: a report from the Children's Oncology Group.

BACKGROUND: Supratentorial PNETs (sPNET) are uncommon embryonal malignancies of the central nervous system whose prognosis has historically been poor. We evaluated the outcome and prognostic factors of children with sPNET treated prospectively on a Children's Oncology Group trial. PROCEDURE: Following surgery, patients received craniospinal radiotherapy with concurrent carboplatin followed by six months of maintenance chemotherapy with cyclophosphamide and vincristine. RESULTS: Five-year overall survival (OS) and progression-free survival (PFS) for all patients was 58 ± 7% and 48 ± 7%. For patients with pineoblastoma (n = 23), five-year OS and PFS was 81 ± 9% and 62 ± 11%. Extent of resection but not M-stage was prognostic. Five-year OS and PFS for 37 patients with non-pineal tumors (NPsPNET) was 44 ± 8% and 39 ± 8%, significantly worse than for PB (P = 0.055 and 0.009 respectively). Extent of resection and major radiotherapy deviations were prognostic. Five year OS was 59 +/- 11.4% for those undergoing complete resection versus 10.4 +/- 7% for those who did not (P = 0.017). Central pathologic review called 14 (38%) "classic" sPNET, 8 (22%) "undifferentiated" and 13 (35%) "malignant gliomas." There was no significant difference between the subgroups, although survival distributions approached significance when the combined "classic" and "undifferentiated" group was compared to the "malignant gliomas." CONCLUSIONS: Carboplatin during RT followed by 6 months of non-intensive chemotherapy is a feasible treatment strategy for patients with sPNET. Aggressive surgical resection should be attempted if feasible. The classification of supratentorial small cell malignancies can be difficult.

Pseudoprogression of low-grade gliomas after radiotherapy.

BACKGROUND: Increasing mass effect following radiation therapy (RT) in patients with low-grade gliomas (LGGs) can be mistaken for tumor progression and/or malignant degeneration. Distinguishing pseudoprogression (PP) from true progression is crucial, with vastly different treatment approaches and prognoses. PROCEDURE: Patients treated with RT for LGGs through the Children's Hospital of Pittsburgh Neuro-Oncology Program are considered to have PP and managed conservatively if they develop increased mass effect within 3 years of RT. Pre-RT tumor area was compared to the maximum tumor size following RT and the size on the last follow-up scan by a central reviewer. RESULTS: Twenty-four children, median age 13 years, received external beam RT for LGG between March 2000 and August 2011. Thirteen patients (54.2%) developed an increase in tumor size compared to baseline beginning at a median of 6 months after RT and lasting for a median of 2.1 years (range 6.5 months to 5.1 years). Maximum tumor enlargement occurred at a median of 8 months after RT, with a range (5 months to 4.2 years). In all 13 cases, the tumor eventually decreased in size without additional anti-tumor therapy. Two patients (8.3%) developed true tumor progression. With a median follow-up of 4.9 years (range 1.0-12.4 years), all patients are alive. CONCLUSIONS: Pseudoprogression occurred in more than half of the children with LGG following RT, typically beginning within 8 months and often running a very protracted course. Late presentations can also occur.

Neurocutaneous melanosis is associated with tethered spinal cord.

PURPOSE: Neurocutaneous melanosis (NCM) is a rare congenital disorder occurring in children born with multiple or large congenital melanocytic nevi (CMN) in association with melanocytic deposits in the leptomeninges. Multiple associations between NCM and other syndromes or neurologic abnormalities have been reported. Of note, there exists a possible association between NCM and tethered cord (TC). METHODS: We retrospectively reviewed charts and films of all patients with the diagnosis of NCM at the Children's Hospital of Pittsburgh (CHP) from August 2002 to present. RESULTS: Five children met the criteria for NCM at our institution over a 12-year period. Apart from the melanocytic deposits, one or more additional spinal abnormalities were identified in all children. Three children had radiographic evidence of a low-lying conus medullaris, two of which also demonstrated lipomatous infiltration of the filum terminale, consistent with a tethered cord (TC). CONCLUSIONS: Clinical features of NCM include dermatologic and neurologic manifestations. To date, this is the first series to note an association between NCM and TC. While nearly all recent series of NCM patients advocate early MRI of the neuroaxis, we recommend screening imaging of the spine on children with possible NCM regardless of the locations of CMN.

Bevacizumab for symptomatic radiation-induced tumor enlargement in pediatric low grade gliomas.

BACKGROUND: Radiation therapy (RT)-induced effects in children treated for low grade glioma (LGG) can result in worsening of neurologic symptoms and clinical and radiographic deterioration. Treatment for radiation-induced tumor enlargement is based on symptom control and usually involves steroids. PROCEDURE: We conducted a retrospective review of children with LGG treated with RT who developed symptomatic radiation-induced tumor enlargement and were managed with bevacizumab. Charts were abstracted for onset and duration of RT changes, toxicity and doses of dexamethasone and bevacizumab. Tumor volumes prior to RT, at maximal size following RT, after bevacizumab administration, and at follow-up were evaluated. RESULTS: Five children were treated with bevacizumab for symptomatic radiation-induced tumor enlargement following RT for LGG at a median of 4.2 months (range, 1-11 months) after completion of RT. The median increase in volume of tumor was 195.4% (range, 115.5-309%) compared to the pre-RT volume. Bevacizumab 5-10 mg/kg was administered IV q 2-4 weeks as primary treatment (n = 1) or to assist in weaning patients off steroids (n = 4). All children on high dose steroids (n = 4) were weaned off or to physiologic doses of hydrocortisone. Two children developed avascular necrosis after prolonged steroid use and while on bevacizumab. Radiographically, all children showed significant improvement and are now a median of 31 months (range, 18-50 months) from the completion of radiation without requiring additional tumor-related therapy. CONCLUSIONS: Bevacizumab can play an important role in children with symptomatic radiation changes following LGG treatment, allowing patients to avoid or minimize the toxicity of long-term steroid use. Pediatr Blood Cancer 2015;62:240-245. © 2014 Wiley Periodicals, Inc.

Antigen-specific immune responses and clinical outcome after vaccination with glioma-associated antigen peptides and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in children with newly diagnosed malignant brainstem and nonbrainstem gliomas.

PURPOSE: Diffuse brainstem gliomas (BSGs) and other high-grade gliomas (HGGs) of childhood carry a dismal prognosis despite current treatments, and new therapies are needed. Having identified a series of glioma-associated antigens (GAAs) commonly overexpressed in pediatric gliomas, we initiated a pilot study of subcutaneous vaccinations with GAA epitope peptides in HLA-A2-positive children with newly diagnosed BSG and HGG. PATIENTS AND METHODS: GAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13Rα2), and survivin, and their peptide epitopes were emulsified in Montanide-ISA-51 and given every 3 weeks with intramuscular polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose for eight courses, followed by booster vaccinations every 6 weeks. Primary end points were safety and T-cell responses against vaccine-targeted GAA epitopes. Treatment response was evaluated clinically and by magnetic resonance imaging. RESULTS: Twenty-six children were enrolled, 14 with newly diagnosed BSG treated with irradiation and 12 with newly diagnosed BSG or HGG treated with irradiation and concurrent chemotherapy. No dose-limiting non-CNS toxicity was encountered. Five children had symptomatic pseudoprogression, which responded to dexamethasone and was associated with prolonged survival. Only two patients had progressive disease during the first two vaccine courses; 19 had stable disease, two had partial responses, one had a minor response, and two had prolonged disease-free status after surgery. Enzyme-linked immunosorbent spot analysis in 21 children showed positive anti-GAA immune responses in 13: to IL-13Rα2 in 10, EphA2 in 11, and survivin in three. CONCLUSION: GAA peptide vaccination in children with gliomas is generally well tolerated and has preliminary evidence of immunologic and clinical responses. Careful monitoring and management of pseudoprogression is essential.

Marked recovery of vision in children with optic pathway gliomas treated with bevacizumab.

IMPORTANCE: Children with optic pathway gliomas (OPGs) frequently experience vision loss from their tumors. Standard front-line treatment using carboplatin-based chemotherapy typically produces only a modest benefit (eg, stabilization or 0.2 logMAR improvement) in visual acuity (VA). Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor and acts primarily as an anti-angiogenic agent. Recent reports suggest a qualitative improvement in vision after bevacizumab-based treatment in children with OPGs. OBSERVATIONS: We report 4 cases of pediatric OPGs (2 neurofibromatosis type 1-related and 2 sporadic cases) that received treatment with bevacizumab due to progressive VA or visual field (VF) loss despite prior treatment with chemotherapy or proton-beam radiation. All 4 subjects demonstrated a marked improvement in their VA, VF, or both while receiving bevacizumab-based therapy. Three patients had complete resolution of their VA or VF loss in at least 1 eye-2 of whom had previously received bevacizumab therapy. CONCLUSIONS AND RELEVANCE: Given that most patients with OPG-related visual impairment will show modest or no visual improvement with standard treatment, the incorporation of bevacizumab in these cases may greatly improve visual outcomes and should be considered in appropriate clinical situations.

Ependymomas: development of immunotherapeutic strategies.

Ependymomas are among the most challenging childhood brain tumors. Although 50-70% of ependymomas are cured with surgery and irradiation, a significant percentage of tumors recur. Ependymomas that are not amenable to complete resection at diagnosis have a particularly poor prognosis, and the vast majority of affected children experience tumor recurrence. Although transient responses have been observed in recurrent tumors treated with re-irradiation and several chemotherapy regimens, long-term disease control is rarely achieved. Children with recurrent disease commonly experience cumulative neurological morbidity from repeated surgical and adjuvant therapy interventions and almost universally succumb to refractory tumor progression. Accordingly, conceptually new treatment approaches are needed, both to decrease the risk of tumor recurrence and to enhance disease control in those children who experience recurrent disease. This article reviews the current application of risk-based treatment stratification at diagnosis, the rationale for exploring the role of novel therapeutic strategies such as immunotherapy at recurrence and the concept behind a vaccine-based trial for these tumors.

LOH in the HLA class I region at 6p21 is associated with shorter survival in newly diagnosed adult glioblastoma.

PURPOSE: Glioblastoma (GBM) shows downregulated expression of human leukocyte antigen (HLA) class I, thereby escaping from cytotoxic T cells and limiting the efficacy of immunotherapy. Loss of heterozygosity (LOH) of HLA class I (6p21) and/or ß-2 microglobulin (B2m) (15q21) regions represents irreversible downregulation. In this study, we examined the prevalence of these LOH events and their relations with overall survival in GBM. EXPERIMENTAL DESIGN: In a cross-sectional analysis on 60 adult patients with GBM, DNA from formalin-fixed, paraffin-embedded specimens were evaluated for 10 microsatellite regions of HLA class I, B2m, HLA class II, HLA class III, and 6q by PCR as well as immunohistochemical evaluation of HLA class I expression and CD8(+) T-cell infiltration. RESULTS: LOH in HLA class I, B2m, HLA class II, HLA class III, and 6q regions was present in 41.4%, 18.2%, 9.4%, 77.8%, and 36.0% of informative cases, respectively. LOH of HLA class I was associated with shorter overall survival (HR = 4.89, P = 0.0078). HLA class I was downregulated in 22% to 43% of cases based on immunohistochemistry. Cases that displayed negative staining were significantly younger. HLA class I expression correlated with intratumoral CD8(+) T-cell infiltration. CONCLUSION: LOH in the HLA class I region is frequent in adult GBMs. The association of shorter survival with LOH in this region suggests a crucial role for these genes in immunosurveillance.