LOGGIC/FIREFLY-2: a phase 3, randomized trial of tovorafenib vs. chemotherapy in pediatric and young adult patients with newly diagnosed low-grade glioma harboring an activating RAF alteration.

BACKGROUND: Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1 study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use. METHODS: LOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients < 25 years of age with pLGG harboring an activating RAF alteration who require first-line systemic therapy. Patients are randomized 1:1 to either tovorafenib, administered once weekly at 420 mg/m2 (not to exceed 600 mg), or investigator's choice of prespecified SoC chemotherapy regimens. The primary objective is to compare ORR between the two treatment arms, as assessed by independent review per RANO-LGG criteria. Secondary objectives include comparisons of progression-free survival, duration of response, safety, neurologic function, and clinical benefit rate. DISCUSSION: The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05566795. Registered on October 4, 2022.

Left atrial 4D flow cardiovascular magnetic resonance: a reproducibility study in sinus rhythm and atrial fibrillation.

BACKGROUND: Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) allows sophisticated quantification of left atrial (LA) blood flow, and could yield novel biomarkers of propensity for intra-cardiac thrombus formation and embolic stroke. As reproducibility is critically important to diagnostic performance, we systematically investigated technical and temporal variation of LA 4D flow in atrial fibrillation (AF) and sinus rhythm (SR). METHODS: Eighty-six subjects (SR, n = 64; AF, n = 22) with wide-ranging stroke risk (CHA2DS2VASc 0-6) underwent LA 4D flow assessment of peak and mean velocity, vorticity, vortex volume, and stasis. Eighty-five (99%) underwent a second acquisition within the same session, and 74 (86%) also returned at 30 (27-35) days for an interval scan. We assessed variability attributable to manual contouring (intra- and inter-observer), and subject repositioning and reacquisition of data, both within the same session (same-day scan-rescan), and over time (interval scan). Within-subject coefficients of variation (CV) and bootstrapped 95% CIs were calculated and compared. RESULTS: Same-day scan-rescan CVs were 6% for peak velocity, 5% for mean velocity, 7% for vorticity, 9% for vortex volume, and 10% for stasis, and were similar between SR and AF subjects (all p > 0.05). Interval-scan variability was similar to same-day scan-rescan variability for peak velocity, vorticity, and vortex volume (all p > 0.05), and higher for stasis and mean velocity (interval scan CVs of 14% and 8%, respectively, both p < 0.05). Longitudinal changes in heart rate and blood pressure at the interval scan in the same subjects were associated with significantly higher variability for LA stasis (p = 0.024), but not for the remaining flow parameters (all p > 0.05). SR subjects showed significantly greater interval-scan variability than AF patients for mean velocity, vortex volume, and stasis (all p < 0.05), but not peak velocity or vorticity (both p > 0.05). CONCLUSIONS: LA peak velocity and vorticity are the most reproducible and temporally stable novel LA 4D flow biomarkers, and are robust to changes in heart rate, blood pressure, and differences in heart rhythm.

Novel predictive scoring system for morbid hypothalamic obesity in patients with pediatric craniopharyngioma.

PURPOSE: To identify the independent risk factors for developing morbid hypothalamic obesity, to propose a predictive scoring system for morbid hypothalamic obesity, and to propose an algorithm for management in order to minimize the risk of developing morbid hypothalamic obesity in patients with pediatric craniopharyngioma. METHODS: A retrospective analysis of all pediatric craniopharyngioma patients diagnosed and treated at Boston Children's Hospital (BCH) between 1985 and 2017. Analysis of the data was conducted using IBM SPSS Statistics. RESULTS: We identified 105 patients, 90 (47 males and 43 females) fulfilled the inclusion criteria. The median age of patients at time of diagnosis was 8.4 years. The median follow-up was 10.6 years. Morbid hypothalamic obesity was evident in 28 (31.1%) patients at the last follow-up visit. Age of patients at time of diagnosis > 10 years (P = 0.023), preoperative body mass index (BMI) > 95th percentile (P = 0.006), and preoperative papilledema (P < 0.001) were the independent risk factors for developing morbid hypothalamic obesity. CONCLUSION: We developed a unique predictive scoring system in order to differentiate between patients with and without high risk for developing morbid hypothalamic obesity.

Sixty years single institutional experience with pediatric craniopharyngioma: between the past and the future.

PURPOSE: To demonstrate the paradigm shift in management strategies of pediatric craniopharyngioma at our institution over the past six decades. METHODS: Retrospective analysis of all pediatric patients with craniopharyngioma treated at Boston Children's Hospital between 1960 and 2017. RESULTS: One hundred seventy-eight patients with craniopharyngioma were treated between 1960 and 2017; 135 (70 males and 65 females) fulfilled the inclusion criteria. Forty-five patients were treated in the old era (1960-1984) and 90 patients were treated in the new era (1985-2017). Gross total resection (GTR) was achieved in 4% and 43% of patients in old and new eras respectively. Sub-total resection (STR) and radiotherapy (XRT) were performed in 27% and 28% of patients in old and new eras respectively. STR without XRT was performed in 20% and 29% of patients in old and new era respectively. Cyst drainage and adjuvant radiotherapy were performed in 49% of patients in the old era while no patients in the new era underwent such conservative management. Aggressive surgical resection was associated with a higher risk of worsening visual outcomes (20% vs 16%), panhypopituitarism and diabetes insipidus (86% vs 53%), psycho-social impairment (42% vs 26%), and new-onset obesity (33% vs 22%). The mortality rate was higher in the old era in comparison with that of the new one (9% vs 2%). CONCLUSION: There was a paradigm shift in management strategies of pediatric craniopharyngioma over the past six decades which in turn affected the long-term outcomes and quality of life of patients.

Increasing value of autopsies in patients with brain tumors in the molecular era.

BACKGROUND: Pediatric brain tumors are associated with high morbidity and mortality, in part due to insufficient understanding of tumor biology. With limited tissue allocation for research from surgical specimens, a key barrier to improving biological understanding, brain tumor autopsies have become an increasingly valuable resource. This study reviews the brain tumor autopsy practice at our institution and describes specific emerging research utilization patterns beyond the clinical autopsy report. METHODS: We performed a retrospective analysis of brain tumor autopsies at Boston Children's Hospital (BCH) between 2007 and 2017 and reviewed their consents, neuropathology reports and final diagnoses. We reviewed the method of tissue triaging for research consented autopsies (bioregistry, frozen and fresh tissue) and documented their specific uses. RESULTS: Ninety-six deaths at BCH were due to brain tumors; 56 autopsies were performed (58.3%), of which 49 (87.5%) were consented for research. Tumor mapping was performed on all cases and tissue was allocated for DNA- and RNA-based sequencing studies (published and ongoing). Three tissue allocations with a postmortem interval of 8 h or less resulted in successful cell lines. Tissue from 14 autopsies was contributed to the National DIPG Registry. CONCLUSION: Our institutional pediatric brain tumor autopsy clinical experience demonstrates the increased utility and wide utilization of autopsy-derived tissue for multiple types of research. These results support the increased efforts to obtain research consent for brain tumor autopsy and active collection of unfixed autopsy material in the molecular era.

Using the Patient-Reported Outcomes Measurement Information System (PROMIS) to measure symptom burden reported by patients with brain tumors.

BACKGROUND: Children with brain tumors can experience symptom burden throughout their disease continuum. The aim of the study was to evaluate symptom burden reported by children with brain tumors and factors that potentially were associated with their symptoms. METHODS: Data from 199 children with brain tumors aged 7-22 (mean age = 14 years; 52% males; 76% white) were analyzed. Symptom burden was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) via computerized adaptive testing (CAT)-anxiety, depression, fatigue, mobility, upper extremity function, peer relationship, and cognition. Patients and parents completed Symptom Distress Scales (SDS). Test statistics and ANOVA were used to evaluate relationships between PROMIS measures and potentially influential variables. RESULTS: Significant results (P < 0.01) showing impact of symptom burden included: PROMIS measures correlated with SDSs reported by patients and parents on all comparisons. Fatigue, mobility, and upper extremity function were associated with Karnofsky functional performance status, number of treatment modalities (0-3), and time since last treatment (≤1 year, >1 year). Fatigue and cognition were associated with educational program (regular classroom without an individualized education plan vs those that had an individualized education plan); mobility and upper extremity function were associated with time since last radiation. Mobility, upper extremity function, and anxiety were associated with time since last chemotherapy. CONCLUSIONS: Significant associations were found between PROMIS and SDS as well as clinical and demographic characteristics. Brief-yet-precise PROMIS CATs can be used to systematically assess symptom burden experienced by children with brain tumors.

The management of childhood cancer survivors at risk for stroke: A Delphi survey of regional experts.

BACKGROUND: Evidence is not available to guide management of childhood cancer survivors (CCS) at risk for radiation-associated cerebral vascular disease (CVD) and stroke. We propose to use a consensus-based methodology to describe the collective opinion of regional experts for the care of these patients and identify areas of controversy. PROCEDURE: Thirty physicians from the New England region who care for CCS participated in a Delphi panel querying their management approach (imaging, laboratory tests, medications, counseling, referrals) to a CCS treated with cranial radiation formatted as five clinical scenarios (asymptomatic, small- and large-vessel CVD, transient ischemia, stroke) in three rounds of anonymous questionnaires. Consensus defined as ≥90% agreement. RESULTS: Response rate was 100% for all three rounds. Panelists reached consensus on laboratory tests to assess stroke risk factors, stroke risk and prevention counseling, brain imaging to monitor survivors with known CVD, and acute care for stroke symptoms. Only 67% panelists agreed with MRI screening asymptomatic survivors with no history of CVD, 87% endorsed aspirin as stroke prevention for large-vessel CVD and 57% for small-vessel CVD. There was no consensus on specialty referrals. Overall, panelists practicing at large institutions and neurology subspecialists were more likely to advocate for screening, interventions, and referrals. CONCLUSIONS: Despite lack of evidence to guide stroke prevention in CCS treated with cranial radiation, a panel of regional physicians reached consensus on managing most clinical scenarios. Controversial areas requiring further study are surveillance imaging for asymptomatic survivors, aspirin for stroke prevention, and indications for specialty referral.

A phase 1/2 dose-finding, safety, and activity study of cabazitaxel in pediatric patients with refractory solid tumors including tumors of the central nervous system.

BACKGROUND: This phase 1/2 study (NCT01751308) evaluated cabazitaxel in pediatric patients. Phase 1 determined the maximum tolerated dose (MTD) in patients with recurrent/refractory solid tumors, including central nervous system (CNS) tumors. Phase 2 evaluated activity in pediatric recurrent high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). PROCEDURE: In phase 1, a 3 + 3 dose-escalation study design was followed. Cabazitaxel was administered at a starting dose of 20 mg/m2 . Dose-limiting toxicities (DLTs) during cycle 1 were assessed to determine the MTD. Tumor response and cabazitaxel pharmacokinetics were also assessed. In phase 2, patients received cabazitaxel at the MTD determined in phase 1. Tumor responses were assessed every 9 weeks (modified Response Assessment in Neuro-oncology criteria). Progression-free survival and cabazitaxel pharmacokinetics were evaluated, and overall survival was estimated. RESULTS: In phase 1, 23 patients were treated, including 19 with CNS tumors. One patient had a partial response; five had stable disease for >3 cycles. Common adverse events included fatigue, diarrhea, nausea and vomiting, febrile neutropenia, and hypersensitivity reactions. Two of three DLTs (febrile neutropenia) occurred with a dose of 35 mg/m2 ; the MTD was 30 mg/m2 . Slightly higher cabazitaxel clearance was observed compared with adult trials. In phase 2, 16 patients (eight HGG and eight DIPG) were enrolled; 11 were evaluable for response and five withdrew (three due to anaphylaxis). All 11 patients progressed within four cycles. No responses were observed; the study was stopped due to futility. CONCLUSIONS: The safety profile of cabazitaxel was consistent with previous studies. The MTD (30 mg/m2 ) was higher than the adult MTD. Cabazitaxel did not demonstrate activity in recurrent/refractory HGG or DIPG.

Rethinking childhood ependymoma: a retrospective, multi-center analysis reveals poor long-term overall survival.

Ependymoma is the third most common brain tumor in children, but there is a paucity of large studies with more than 10 years of follow-up examining the long-term survival and recurrence patterns of this disease. We conducted a retrospective chart review of 103 pediatric patients with WHO Grades II/III intracranial ependymoma, who were treated at Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Chicago's Ann & Robert H. Lurie Children's Hospital between 1985 and 2008, and an additional 360 ependymoma patients identified from the Surveillance Epidemiology and End Results (SEER) database. For the institutional cohort, we evaluated clinical and histopathological prognostic factors of overall survival (OS) and progression-free survival (PFS) using the log-rank test, and univariate and multivariate Cox proportional-hazards models. Overall survival rates were compared to those of the SEER cohort. Median follow-up time was 11 years. Ten-year OS and PFS were 50 ± 5% and 29 ± 5%, respectively. Findings were validated in the independent SEER cohort, with 10-year OS rates of 52 ± 3%. GTR and grade II pathology were associated with significantly improved OS. However, GTR was not curative for all children. Ten-year OS for patients treated with a GTR was 61 ± 7% and PFS was 36 ± 6%. Pathological examination confirmed most recurrent tumors to be ependymoma, and 74% occurred at the primary tumor site. Current treatment paradigms are not sufficient to provide long-term cure for children with ependymoma. Our findings highlight the urgent need to develop novel treatment approaches for this devastating disease.

Discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity and pharmacokinetics.

Selective inhibition of Kv1.5, which underlies the ultra-rapid delayed rectifier current, IKur, has been pursued as a treatment for atrial fibrillation. Here we describe the discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity versus the off-target current IKs, whose inhibition has been associated with ventricular proarrhythmia. MK-1832 exhibits improved selectivity for IKur over IKs (>3000-fold versus 70-fold for MK-0448), consistent with an observed larger window between atrial and ventricular effects in vivo (>1800-fold versus 210-fold for MK-0448). MK-1832 also exhibits an improved preclinical pharmacokinetic profile consistent with projected once daily dosing in humans.

Brain tumors and epileptic spasms: Natural history and outcomes.

While brain tumors are a frequent cause of seizures, they rarely cause epileptic spasms (ES). The objective of this study was to investigate features of tumor-associated ES. We conducted a retrospective review of patients with ES and a brain tumor. Demographics; pathologic, radiologic, and EEG data; treatment response; and long-term outcome were collected. Twenty four patients were identified; 11 met inclusion criteria. Epileptic spasm (ES) onset occurred prior to tumor diagnosis in seven patients (63%), and after tumor resection in 4 patients (36%). Spasms and ictal EEG often had focal features (45%). Gross total tumor resection resulted in ES freedom in 3/7 patients. There was poor response to first-line therapy (ACTH/vigabatrin; 1/5 with ES freedom). Low grade tumors predominated (8/11) with dual pathology (associated cortical malformation) in 2 patients. All tumors involved cortex; half involved subcortical regions and/or brainstem. Ten patients developed other seizure types; eight experienced refractory epilepsy, and nine had a Modified Rankin Scale of >3. In summary, EEG in tumor-associated ES often has focal features of either the semiology or EEG. Complete tumor resection yielded ES freedom in only a subset of patients. Most patients developed refractory epilepsy and adverse developmental outcomes.

Successful Treatment of Recurrent Li-Fraumeni Syndrome-related Choroid Plexus Carcinoma.

The management of choroid plexus carcinoma (CPC) is challenging and multifaceted. Here, we discuss a 3-year-old girl with CPC and Li-Fraumeni syndrome who achieved full remission after surgery and chemotherapy, with radiation therapy spared. At recurrence, we used a novel, standard-dose cytotoxic chemotherapy regimen, focal proton radiation therapy, and targeted agents based on morphoproteomic analysis to achieve long-term survival. We highlight the rationale for our therapy at recurrence, as well as the risk-benefit analyses necessary in decision making for these patients. Our strategy may be effective in managing other patients with recurrent CPC and Li-Fraumeni syndrome.

Adapted Delivery of Cognitive-Behavioral Treatment for Insomnia in Adolescent and Young Adult Cancer Survivors: A Pilot Study.

Adolescent and young adult cancer survivors (AYACS) are at risk for the development of insomnia, though it remains vastly undertreated. Limited research has evaluated cognitive-behavioral treatment for insomnia (CBT-I) in AYACS. The present study piloted adapted CBT-I designed to improve treatment accessibility by delivering a three-session intervention in person and via videoconference. AYACS with insomnia (N = 12) enrolled in the study. Ten AYACS completed the intervention, with six in person and four via videoconference. Sleep variables improved immediately postintervention and were sustained at two-month follow-up. Within sample effect sizes of the adapted intervention for sleep, variables were large, and there were no noted differences on sleep outcomes between the in-person and videoconference participants. These pilot findings indicate that an adapted CBT-I intervention is feasible and promising in AYACS populations.

Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: A population-based study.

BACKGROUND: The determinants of outcomes for adult survivors of pediatric low-grade glioma (PLGG) are largely unknown. METHODS: This study collected population-based follow-up information for all PLGG patients diagnosed in Ontario, Canada from 1985 to 2012 (n = 1202) and determined factors affecting survival. The impact of upfront radiation treatment on overall survival (OS) was determined for a cohort of Ontario patients and an independent reference cohort from the Surveillance, Epidemiology, and End Results database. RESULTS: At a median follow-up of 12.73 years (range, 0.02-33 years), only 93 deaths (7.7%) were recorded, and the 20-year OS rate was 90.1% ± 1.1%. Children with neurofibromatosis type 1 had excellent survival and no tumor-related deaths during adulthood. Adverse risk factors included pleomorphic xanthoastrocytoma (P < .001) and a thalamic location (P < .001). For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3-fold increased risk of overall late deaths (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6-6.6; P = .001) and an approximately 4-fold increased risk of tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = .013). In a multivariate analysis, radiotherapy was the most significant factor associated with late all-cause deaths (HR, 3.0; 95% CI, 1.3-7.0; P = .012) and tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = 0.014). A similar association between radiotherapy and late deaths was observed in the independent reference cohort (P < .001). In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non-oncological causes. CONCLUSIONS: The course of PLGG is associated with excellent long-term survival, but this is hampered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients.

Long-term visual outcomes of optic pathway gliomas in pediatric patients without neurofibromatosis type 1.

Sporadic optic pathway gliomas (OPGs) have been reported to cause more vision loss than OPGs associated with neurofibromatosis type-1, but long-term visual outcome data are limited. The purpose of this study was to report the visual outcomes of a cohort of pediatric patients with sporadic OPGs. This was a retrospective, cohort study at a tertiary care pediatric hospital and cancer institute. The study included all patients with sporadic OPGs evaluated from 1990 to 2014. The primary outcome was visual acuity at final follow-up. Secondary outcomes were risk factors for a poor visual outcome and the rate of progression. There were 59 pediatric patients included in the study. Median age at presentation was 2.5 years old and median follow-up was 5.2 years. In the worse eye at final follow-up, 16 patients (27 %) were 20/30 or better, 9 patients (15 %) were between 20/40 and 20/80, and 34 patients (58 %) were 20/100 or worse. In the better eye at final follow-up, 33 patients (56 %) were 20/30 or better, 11 patients (19 %) were between 20/40 and 20/80, and 15 patients (25 %) were 20/100 or worse. Risk factors for a poor visual outcome included younger age at presentation, optic nerve pallor, and tumor extent. Of the 54 patients (92 %) who received treatment, 40 (74 %) experienced disease progression during or after treatment. A majority of pediatric patients with sporadic OPGs had significant long-term visual impairment. In spite of treatment, tumor progression is common. Serial ophthalmic examinations with quantitative vision measurements are essential in the management of sporadic OPGs.

Disseminated glioneuronal tumors occurring in childhood: treatment outcomes and BRAF alterations including V600E mutation.

Disseminated glioneuronal tumors of childhood are rare. We present a retrospective IRB-approved review of the clinical course and frequency of BRAF mutations in disseminated glioneuronal tumors at two institutions. Defining features of our cohort include diffuse leptomeningeal-spread, often with a discrete spinal cord nodule and oligodendroglioma-like histologic features. Patients were identified through a pathology database search of all cases with disseminated low-grade neoplasms with an oligodendroglioma-like component. De-identified clinical information was collected by chart review and all imaging was reviewed. We retrieved the results of targeted genomic analyses for alterations in BRAF. Ten patients (aged 2-14 years) were identified from the Dana-Farber/Boston Children's Hospital and the Royal Children's Hospital, Melbourne pathology databases. Nine patients received chemotherapy. Eight patients are alive, although three have had episodes of progressive disease. We identified genomic alterations affecting the MAPK pathway in six patients. One patient had a germline RAF1 mutation and a clinical diagnosis of cardio-facio-cutaneous syndrome. BRAF duplications were identified in four and BRAF V600E mutation was identified in one. These data support the presence of targetable genomic alterations in this disease.

Myxopapillary ependymomas in children: imaging, treatment and outcomes.

Myxopapillary ependymomas (MPEs) are rare spinal tumors in children. The natural history and clinical course of pediatric MPEs are largely unknown and the indication for adjuvant therapy remains to be clarified. We performed an IRB-approved, retrospective review of children with MPEs treated at the Dana-Farber/Boston Children's Cancer and Blood Disorder Center between 1982 and 2013. Eighteen children (age range 8-21 years, median age 14 years) met inclusion criteria. We reviewed the histopathology, magnetic resonance imaging, tumor location and stage, surgical management, adjuvant therapy, and clinical outcomes. The median follow-up duration was 9.4 years (range 1-30 years). Children most commonly presented with pain, scoliosis, and urinary symptoms. All primary tumors were located in the lower thoracic or lumbar spine. Nine children (50%) had leptomeningeal tumor seeding at presentation, most commonly located within the distal thecal sac. A gross-total resection was achieved in nine children (50%). Three children were treated with irradiation following initial surgery. No child received adjuvant chemotherapy at diagnosis. The 10-year event-free survival (EFS) was 26% ± 14.8. Children with disseminated disease trended towards inferior EFS compared to those with localized disease (10-year EFS 12.7% ± 12 vs. 57 ± 25%, p value 0.07). The 10-year overall survival was 100%. The efficacy of adjuvant irradiation could not be assessed due to the small sample size. Although children with MPEs frequently present with disseminated tumor and/or develop recurrent or progressive disease, their overall survival is excellent. Treatment should aim to minimize both tumor- and therapy-related morbidity.

Visual Field Loss in a Case of Recurrent Cystic Craniopharyngioma During Concomitant Treatment With Pegylated Interferon α-2b.

A 13-year-old male with suprasellar cystic craniopharyngioma initially controlled with sequential subtotal resections and proton-beam irradiation was later treated with intracystic pegylated interferon α-2b due to progression and a lack of further surgical options. After initial successful control of recurrent cyst enlargement and stabilization of the ophthalmic examination, progressive and irreversible visual field loss ensued. Imaging revealed intracranial leakage from the intracystic catheter, and direct administration of interferon α-2b was discontinued. Given the recent interest in interferon α-2b, oncologists are advised to vigilantly monitor patients for signs of local toxicity that may result from unintended leakage during intracystic delivery.

Central Versus Extraventricular Neurocytoma in Children: A Clinicopathologic Comparison and Review of the Literature.

BACKGROUND: Central neurocytomas (CN) are rare pediatric CNS tumors most often with a benign clinical course. Occasionally, these tumors occur outside the ventricles and are called extraventricular neurocytomas (EVN). We present a retrospective institutional analysis of children with neurocytoma with prolonged follow-up. PROCEDURE: Twelve patients were diagnosed with neurocytoma at our institution between 1993 and 2004. RESULTS: Six patients were male and the median age at diagnosis was 12 years (1.5 to 16 y). Seven patients had CN and 5 had EVN. Presenting symptoms included headaches (67%), vomiting (50%), nausea (33%), seizures (33%), and mental status changes (25%). Obstructive hydrocephalus was present at diagnosis in 42% of the cases. Younger age and seizures were more common in patients with EVN. Gross total resection (GTR) was achieved in 42% (5/12) of the patients. Patients with GTR received no adjuvant therapy upfront; 1 patient subsequently had recurrence with leptomeningeal disease. Patients with subtotal resection received additional treatment: 1 underwent reoperation (GTR), 2 patients received focal radiation, 2 patients received adjuvant chemotherapy, and 2 patients received craniospinal irradiation followed by chemotherapy. The 20-year overall survival for this cohort was 83% with event free survival of 56%. Overall survival for CNs was 100%, versus 40% for EVN. Event free survival for CNs was 57% and 53% for the EVNs. An MIB-1 fraction >2% was associated with worse prognosis. CONCLUSIONS: Neurocytomas are rare brain tumors in children usually cured with GTR. Adjuvant focal radiation therapy and/or chemotherapy may improve disease control in cases with subtotal resection, but case-by-case analysis should be done. EVNs might be associated with worse outcome due to a higher proliferative index.

Screening for fatigue in adolescent and young adult pediatric brain tumor survivors: accuracy of a single-item screening measure.

PURPOSE: Cancer-related fatigue (CRF) is one of the most commonly reported and distressing symptoms experienced by adolescent and young adult (AYA) cancer survivors. While national guidelines have recommended screening for CRF during routine follow-up appointments, the validity of using a one-item screening measure for fatigue has not been examined with AYA brain tumor survivors. The purpose of this study is to assess how well a single-item fatigue screen could identify clinically significant fatigue in childhood brain tumor survivors. METHODS: A single-item measure, the Fatigue Thermometer (FT), was compared with a more in-depth measure, the Multidimensional Fatigue Scale (MFS), in a cohort of AYA pediatric brain tumor survivors. One hundred and forty-two survivors (aged 12-32 years) completed the two instruments. RESULTS: Forty-two survivors were identified on the MFS as having clinically significant fatigue, but the FT was not found to be an accurate tool for identifying these cases. Although receiver operating characteristic curve analysis of FT ratings against the MFS criterion indicated good concordance between measures, no cutoff score on the FT was identified that resulted in acceptable sensitivity and specificity. CONCLUSIONS: Results from this study suggest that a single-item screening measure for fatigue is not able to reliably identify clinically significant fatigue in AYA brain tumor survivors.