Incidence and survival trends for medulloblastomas in the United States from 2001 to 2013.

Population-based data examining recent epidemiological trends in medulloblastoma, the most common pediatric brain malignancy, are limited. Therefore, we sought to examine recent population-level trends in medulloblastoma incidence and survival. Central Brain Tumor Registry of the United States (CBTRUS) data were analyzed from 2001 to 2013. Age-adjusted incidence rates (IR) and annual percent changes (APCs) with 95% confidence intervals (CI) were calculated by age, sex, and race. Relative survival rates were calculated by age, sex, and race using Surveillance, Epidemiology and End-Results (SEER) registries; subsets of CBTRUS data. Kaplan-Meier and Cox proportional hazards models were used to examine survival differences. Medulloblastoma incidence remained relatively stable from 2001 to 2013, with minor fluctuations from 2001 to 2009 (APC = 2.2, 95% CI 0.8, 3.5) and 2009-2013 (APC = -4.1, 95% CI -7.5, -0.6). Incidence was highest in patients aged 1-4 years at diagnosis, but patients aged 10-14 years showed increased incidence from 2000 to 2013 (APC = 3.2, 95% CI 0.6, 5.8). Males displayed higher IR relative to females (males: 0.16 vs. females: 0.12), except in patients <1 year-old. Compared to Whites, Blacks displayed a non-significant increase in incidence (APC = 1.7, 95% CI -0.4, 4.0) and in mortality risk (hazard ratio for survival = 0.74; p = 0.09). The current study reports no overall change in medulloblastoma incidence from 2001 to 2013. Male and female patients <1 year-old had equal medulloblastoma incidence rates and poor 5-year relative survival compared to other ages. Non-significant trends in the data suggest disparities in medulloblastoma incidence and survival by race. Thus, analysis of tumor-specific trends by demographic variables can uncover clinically informative trends in cancer burden.

Optic Pathway Gliomas in Neurofibromatosis Type 1: An Update: Surveillance, Treatment Indications, and Biomarkers of Vision.

Optic pathway gliomas (OPGs) occur in 15%-20% of children with neurofibromatosis type 1 (NF1), leading to visual deficits in fewer than half of these individuals. The goal of chemotherapy is to preserve vision, but vision loss in NF1-associated OPG can be unpredictable. Determining which child would benefit from chemotherapy and, equally important, which child is better observed without treatment can be difficult. Unfortunately, despite frequent imaging and ophthalmologic evaluations, some children experience progressive vision loss before treatment. Indications for chemotherapy usually are based on a comprehensive, quantitative assessment of vision, but reliable vision evaluation can be challenging in young children with NF1-OPG. The ability to identify and predict impending vision loss could potentially improve management decisions and visual outcomes. To address this challenge, ophthalmologic, electrophysiologic, and imaging biomarkers of vision in NF1-OPG have been proposed. We review current recommendations for the surveillance of children at risk for NF1-OPG, outline guidelines for initiating therapy, and describe the utility of proposed biomarkers for vision.

Impact of vision loss among survivors of childhood central nervous system astroglial tumors.

BACKGROUND: The impact of impaired vision on cognitive and psychosocial outcomes among long-term survivors of childhood low-grade gliomas has not been investigated previously but could inform therapeutic decision making. METHODS: Data from the Childhood Cancer Survivor Study were used to investigate psychological outcomes (measures of cognitive/emotional function) and socioeconomic outcomes (education, income, employment, marital status, and independent living) among astroglial tumor survivors grouped by 1) vision without impairment, 2) vision with impairment (including unilateral blindness, visual field deficits, and amblyopia), or 3) bilateral blindness. The effect of vision status on outcomes was examined with multivariate logistic regression with adjustments for age, sex, cranial radiation therapy, and medical comorbidities. RESULTS: Among 1233 survivors of childhood astroglial tumors 5 or more years after their diagnosis, 277 (22.5%) had visual impairment. In a multivariate analysis, survivors with bilateral blindness were more likely to be unmarried (adjusted odds ratio (OR), 4.7; 95% confidence interval [CI], 1.5-15.0), live with a caregiver (adjusted OR, 3.1; 95% CI, 1.3-7.5), and be unemployed (adjusted OR, 2.2; 95% CI, 1.1-4.5) in comparison with those without visual impairment. Bilateral blindness had no measurable effect on cognitive or emotional outcomes, and vision with impairment was not significantly associated with any psychological or socioeconomic outcomes. CONCLUSIONS: Adult survivors of childhood astroglial tumors with bilateral blindness were more likely to live unmarried and dependently and to be unemployed. Survivors with visual impairment but some remaining vision did not differ significantly with respect to psychological function and socioeconomic status from those without visual impairment. Cancer 2016;122:730-739. © 2016 American Cancer Society.

Trends in central nervous system tumor incidence relative to other common cancers in adults, adolescents, and children in the United States, 2000 to 2010.

BACKGROUND: Time trends in cancer incidence rates (IR) are important to measure the changing burden of cancer on a population over time. The overall IR of cancer in the United States is declining. Although central nervous system tumors (CNST) are rare, they contribute disproportionately to mortality and morbidity. In this analysis, the authors examined trends in the incidence of the most common cancers and CNST between 2000 and 2010. METHODS: The current analysis used data from the United States Cancer Statistics publication and the Central Brain Tumor Registry of the United States. Age-adjusted IR per 100,000 population with 95% confidence intervals and the annual percent change (APC) with 95% confidence intervals were calculated for selected common cancers and CNST overall and by age, sex, race/ethnicity, selected histologies, and malignancy status. RESULTS: In adults, there were significant decreases in colon (2000-2010: APC, -3.1), breast (2000-2010: APC, -0.8), lung (2000-2010: APC, -1.1), and prostate (2000-2010: APC, -2.4) cancer as well as malignant CNST (2008-2010: APC, -3.1), but a significant increase was noted in nonmalignant CNST (2004-2010: APC, 2.7). In adolescents, there were significant increases in malignant CNST (2000-2008: APC, 1.0) and nonmalignant CNST (2004-2010: APC, 3.9). In children, there were significant increases in acute lymphocytic leukemia (2000-2010: APC, 1.0), non-Hodgkin lymphoma (2000-2010: APC, 0.6), and malignant CNST (2000-2010: APC, 0.6). CONCLUSIONS: Surveillance of IR trends is an important way to measure the changing public health and economic burden of cancer. In the current study, there were significant decreases noted in the incidence of adult cancer, whereas adolescent and childhood cancer IR were either stable or increasing.

Evolving therapies, neurocognitive outcomes, and functional independence in adult survivors of childhood glioma.

BACKGROUND: Treatment of childhood glioma has evolved to reduce radiotherapy exposure with the goal of limiting late toxicity. However, the associations between treatment changes and neurocognition, and the contribution of neurocognition and chronic health conditions to attainment of adult independence, remain unknown. METHODS: Adult survivors of childhood glioma diagnosed in 1970-1999 in the Childhood Cancer Survivor Study (n = 1284; median [minimum-maximum] 30 [18-51] years of age at assessment; 22 [15-34] years from diagnosis) self-reported neurocognitive impairment and chronic health conditions. Multivariable models evaluated associations between changes in treatment exposures (surgery only, chemotherapy [with or without surgery], cranial radiation [with or without chemotherapy and/or surgery]), and neurocognitive impairment. Latent class analysis with 5 indicators (employment, independent living, assistance with routine and/or personal care needs, driver's license, marital or partner status) identified classes of functional independence. Path analysis tested associations among treatment exposures, neurocognitive impairment, chronic health conditions, and functional independence. Statistical tests were 2-sided. RESULTS: Cranial radiation exposure decreased over time (51%, 1970s; 46%, 1980s; 27%, 1990s]. However, compared with siblings, survivors with any treatment exposure were at elevated risk for neurocognitive impairment, including surgery only (eg, memory: relative risk = 2.22; task efficiency: relative risk = 1.88; both P < .001). Three classes of functional independence were identified: independent (58%), moderately independent (20%), and nonindependent (22%). Cranial radiation was associated with nonindependence through impaired task efficiency (ß = 0.06), sensorimotor (ß = 0.06), and endocrine (ß = 0.10) chronic health conditions and through the associations between these conditions and task efficiency (each ß = 0.04). Sensorimotor and endocrine chronic health conditions were associated with nonindependence through memory. CONCLUSION: Most long-term glioma survivors achieve adult independence. However, functional nonindependence is associated with treatment-related neurocognitive impairment and chronic health conditions.

Neurocognitive outcomes and functional independence in adult survivors of childhood medulloblastoma diagnosed over three decades.

BACKGROUND: Treatment of childhood medulloblastoma has evolved to reduce neurotoxicity while improving survival. However, the impact of evolving therapies on late neurocognitive outcomes and adult functional independence remains unknown. METHODS: Adult survivors of childhood medulloblastoma (n=505; median[minimum-maximum] age, 29[18-46] years) and sibling controls (n=727; 32[18-58] years) from the Childhood Cancer Survivor Study completed surveys assessing neurocognitive problems and chronic health conditions (CHCs). Treatment exposures were categorized as historical (craniospinal irradiation [CSI]≥30 Gy, no chemotherapy), standard-risk (CSI>0 to <30 Gy +chemotherapy) and high-risk (CSI≥30 Gy +chemotherapy) therapy. Latent class analysis identified patterns of functional independence using employment, independent living, assistance with routine/personal care needs, driver's license, marital/partner status. Multivariable models estimated risk of neurocognitive impairment in survivors versus siblings and by treatment exposure group, and associations between neurocognitive impairment, CHCs, and functional independence. RESULTS: Survivors in each treatment exposure group had 4- to 5-fold elevated risk of impaired memory and task efficiency compared to siblings. Contemporary risk-based therapies did not confer lower risk compared to historical therapy. Survivors treated in the 1990s had higher risk of memory impairment (relative risk [RR] 2.24, 95% confidence interval [CI] 1.39-3.60) compared to survivors treated in the 1970s. Sensorimotor, hearing problems and seizures were associated with 33%-34%, 25-26% and 21%-42% elevated risk of task efficiency and memory impairment, respectively. Treatment-related CHCs and neurocognitive impairment were associated with non-independence. CONCLUSIONS: Despite treatment changes, long-term survivors of childhood medulloblastoma remain at risk for neurocognitive impairment, which was associated with CHCs. Neurocognitive surveillance after contemporary regimens is imperative.

Temporal changes in treatment and late mortality and morbidity in adult survivors of childhood glioma: a report from the Childhood Cancer Survivor Study.

Pediatric glioma therapy has evolved to delay or eliminate radiation for low-grade tumors. This study examined these temporal changes in therapy with long-term outcomes in adult survivors of childhood glioma. Among 2,501 5-year survivors of glioma in the Childhood Cancer Survivor Study diagnosed 1970-1999, exposure to radiation decreased over time. Survivors from more recent eras were at lower risk of late mortality (≥5 years from diagnosis), severe/disabling/life-threatening chronic health conditions (CHCs) and subsequent neoplasms (SNs). Adjusting for treatment exposure (surgery only, chemotherapy, or any cranial radiation) attenuated this risk (for example, CHCs (1990s versus 1970s), relative risk (95% confidence interval), 0.63 (0.49-0.80) without adjustment versus 0.93 (0.72-1.20) with adjustment). Compared to surgery alone, radiation was associated with greater than four times the risk of late mortality, CHCs and SNs. Evolving therapy, particularly avoidance of cranial radiation, has improved late outcomes for childhood glioma survivors without increased risk for late recurrence.

MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus.

The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 have made it the first medical therapy approved for this indication in the United States, the European Union, and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefits for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low-grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts.

A rare case of ectopic recurrence of a craniopharyngioma diagnosed 17 years after initial presentation.

Ectopic recurrence of craniopharyngioma 17 years after initial diagnosis is exceedingly rare in pediatric neuro-oncology. Only 23 cases of ectopic recurrence in children with craniopharyngioma are described in the literature with a median time to recurrence of 3 years. We describe a patient diagnosed at 5 years of age, presenting with neck pain and ataxia 17 years after diagnosis. Her original follow-up care was fragmented and included surveillance imaging for 10 years after surgery and endocrine management of panhypopituitarism. Rare, extremely late relapse of this tumor highlights the importance of extended multidisciplinary follow-up care that includes neuro-oncologists in a late-effects/survivorship program.

Years of life lived with disease and years of potential life lost in children who die of cancer in the United States, 2009.

Incidence and survival rates are commonly reported statistics, but these may fail to capture the full impact of childhood cancers. We describe the years of potential life lost (YPLL) and years of life lived with disease (YLLD) in children and adolescents who died of cancer in the United States to estimate the impact of childhood cancer in the United States in 2009. We examined mortality data in 2009 among children and adolescents <20 years old in both the National Vital Statistics System (NVSS) and the Surveillance, Epidemiology, and End Results (SEER) datasets. YPLL and YLLD were calculated for all deaths due to cancer. Histology-specific YPLL and YLLD of central nervous system (CNS) tumors, leukemia, and lymphoma were estimated using SEER. There were 2233 deaths and 153,390.4 YPLL due to neoplasm in 2009. CNS tumors were the largest cause of YPLL (31%) among deaths due to cancer and were the cause of 1.4% of YPLL due to all causes. For specific histologies, the greatest mean YPLL per death was due to atypical teratoid/rhabdoid tumor (78.0 years lost). The histology with the highest mean YLLD per death in children and adolescents who died of cancer was primitive neuroectodermal tumor (4.6 years lived). CNS tumors are the most common solid malignancy in individuals <20 years old and have the highest YPLL cost of all cancers. This offers the first histology-specific description of YPLL in children and adolescents and proposes a new measure of cancer impact, YLLD, in individuals who die of their disease. YPLL and YLLD complement traditional indicators of mortality and help place CNS tumors in the context of other childhood malignancies.

Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007-2011.

The CBTRUS Statistical Report: Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007­2011 comprehensively describes the current population-based incidence of primary malignant and non-malignant brain and CNS tumors in children ages 0­14 years, collected and reported by central cancer registries covering approximately 99.8% of the United States population (for 2011 only, data were available for 50 out of 51 registries). Overall, brain and CNS tumors are the most common solid tumor, the most common cancer, and the most common cause of cancer death in infants and children 0­14 years. This report aims to serve as a useful resource for researchers, clinicians, patients, and families.

Anti-N-methyl-D-aspartate receptor-mediated encephalitis in infants and toddlers: case report and review of the literature.

BACKGROUND: Anti-N-methyl-D-aspartate receptor encephalitis is an increasingly well-recognized inflammatory encephalitis in children and adults. PATIENT: We report a previously healthy 21-month-old girl who presented with behavioral change, self-mutilatory behavior, and echolalia. Over the ensuing weeks, symptoms progressed to include unilateral upper extremity dystonia, gait impairment, dysphagia, and mutism. Magnetic resonance imaging of the brain showed a tiny area of signal abnormality in the subcortical white matter, but was otherwise normal. Continuous video electroencephalography showed slowing of the background rhythm, but was without epileptiform discharges. Lumbar puncture showed a mild pleocytosis of mixed cellularity; bacterial culture and testing for various viral encephalitides were negative. Serum and cerebrospinal fluid was positive for autoantibodies directed against the N-methyl-D-aspartate receptor, and she was diagnosed with anti-N-methyl-D-aspartate receptor encephalitis. The patient was successfully treated with a regimen of immunotherapy that included dexamethasone, intravenous immunoglobulin, and rituximab. One year after initial presentation, the patient remained symptom-free. We further review the clinical characteristics, results of diagnostic studies, treatment, and outcome of infants and toddlers diagnosed with anti-N-methyl-D-aspartate receptor encephalitis that have been previously reported in the literature. CONCLUSION: Anti-N-methyl-D-aspartate receptor encephalitis is relatively common among infants and toddlers and often presents with a pattern of defining characteristics in this age group, particularly the absence of associated tumor.