Correction: Hom et al. Cognitive Function during the Prodromal Stage of Alzheimer's Disease in Down Syndrome: Comparing Models. BrainSci. 2021, 11, 1220.

We would like to submit the following correction to our recently published paper [...].

Evaluation of Upper Airway Stimulation for Adolescents With Down Syndrome and Obstructive Sleep Apnea.

Importance: Patients with Down syndrome have a high incidence of persistent obstructive sleep apnea (OSA) and limited treatment options. Upper airway hypoglossal stimulation has been shown to be effective for adults with OSA but has not yet been evaluated for pediatric populations. Objective: To evaluate the safety and effectiveness of upper airway stimulation for adolescent patients with Down syndrome and severe OSA. Design, Setting, and Participants: This prospective single-group multicenter cohort study with 1-year follow-up was conducted between April 1, 2015, and July 31, 2021, among a referred sample of 42 consecutive adolescent patients with Down syndrome and persistent severe OSA after adenotonsillectomy. Intervention: Upper airway stimulation. Main Outcomes and Measures: The prespecified primary outcomes were safety and the change in apnea-hypopnea index (AHI) from baseline to 12 months postoperatively. Polysomnographic and quality of life outcomes were assessed at 1, 2, 6, and 12 months postoperatively. Results: Among the 42 patients (28 male patients [66.7%]; mean [SD] age, 15.1 [3.0] years), there was a mean (SD) decrease in AHI of 12.9 (13.2) events/h (95% CI, -17.0 to -8.7 events/h). With the use of a therapy response definition of a 50% decrease in AHI, the 12-month response rate was 65.9% (27 of 41), and 73.2% of patients (30 of 41) had a 12-month AHI of less than 10 events/h. The most common complication was temporary tongue or oral discomfort, which occurred in 5 patients (11.9%). The reoperation rate was 4.8% (n = 2). The mean (SD) improvement in the OSA-18 total score was 34.8 (20.3) (95% CI, -42.1 to -27.5), and the mean (SD) improvement in the Epworth Sleepiness Scale score was 5.1 (6.9) (95% CI, -7.4 to -2.8). The mean (SD) duration of nightly therapy was 9.0 (1.8) hours, with 40 patients (95.2%) using the device at least 4 hours a night. Conclusions and Relevance: Upper airway stimulation was able to be safely performed for 42 adolescents who had Down syndrome and persistent severe OSA after adenotonsillectomy with positive airway pressure intolerance. There was an acceptable adverse event profile with high rates of therapy response and quality of life improvement. Trial Registration: ClinicalTrials.gov Identifier: NCT02344108.

Feasibility and Acceptance of Direct-to-Home Tele-neuropsychology Services during the COVID-19 Pandemic.

OBJECTIVE: Neuropsychological assessment via video conferencing has been proposed during the COVID-19 pandemic. Existing literature has demonstrated feasibility and acceptance of neuropsychological measures administered by videoconference, although few studies have examined feasibility and patient acceptance of TNP visits directly to patients' homes (DTH-TNP). METHODS: We modified a previously published patient satisfaction survey for DTH-TNP and developed a clinician feasibility survey to examine experiences during DTH-TNP. RESULTS: Seventy-two patients (age range: preschool-geriatric) evaluated by DTH-TNP for cognitive problems at an academic medical center responded to voluntary surveys between April 20, 2020, and August 19, 2020, and 100% indicated satisfaction. Fifty-nine percent of patients reported limitations (e.g., technological concern) during the appointment. 134 clinician surveys were collected and indicated that clinicians achieved the goal of their appointment in 90% of encounters. CONCLUSIONS: These qualitative data suggest that patients and clinicians found DTH-TNP to be satisfactory during the COVID-19 pandemic, while also recognizing limitations of the practice. These results are limited in that voluntary surveys are subject to bias. They support the growing body of literature suggesting that DTH-TNP provides a valuable service, though additional research to establish reliability and validity is needed.

Cognitive Function during the Prodromal Stage of Alzheimer's Disease in Down Syndrome: Comparing Models.

Accurate identification of the prodromal stage of Alzheimer's disease (AD), known as mild cognitive impairment (MCI), in adults with Down syndrome (MCI-DS) has been challenging because there are no established diagnostic criteria that can be applied for people with lifelong intellectual disabilities (ID). As such, the sequence of cognitive decline in adults with DS has been difficult to ascertain, and it is possible that domain constructs characterizing cognitive function in neurotypical adults do not generalize to this high-risk population. The present study examined associations among multiple measures of cognitive function in adults with DS, either prior to or during the prodromal stage of AD to determine, through multiple statistical techniques, the measures that reflected the same underlying domains of processing. Participants included 144 adults with DS 40-82 years of age, all enrolled in a larger, multidisciplinary study examining biomarkers of AD in adults with DS. All participants had mild or moderate lifelong intellectual disabilities. Overall AD-related clinical status was rated for each individual during a personalized consensus conference that considered performance as well as health status, with 103 participants considered cognitively stable (CS) and 41 to have MCI-DS. Analyses of 17 variables derived from 10 tests of cognition indicated that performance reflected three underlying factors: language/executive function, memory, and visuomotor. All three domain composite scores significantly predicted MCI-DS status. Based upon path modeling, the language/executive function composite score was the most affected by prodromal AD. However, based upon structural equation modeling, tests assessing the latent construct of memory were the most impacted, followed by those assessing visuomotor, and then those assessing language/executive function. Our study provides clear evidence that cognitive functioning in older adults with DS can be characterized at the cognitive domain level, but the statistical methods selected and the inclusion or exclusion of certain covariates may lead to different conclusions. Best practice requires investigators to understand the internal structure of their variables and to provide evidence that their variables assess their intended constructs.

The development and implementation of teleneuropsychology in an academic lifespan neuropsychology center: Lessons learned from the COVID-19 pandemic.

INTRODUCTION: Teleneuropsychology (TNP) became a critical means for providing care during the COVID-19 pandemic and may continue as an option for delivery of neuropsychological services. To understand how patient characteristics impact clinician decisions and service models, this study examines practice patterns within a lifespan outpatient neuropsychology center before, during and post-pandemic. METHODS: Patient volume, demographics, and characteristics were compared across four, 3-month time intervals in 2019-2020. Two baseline intervals when the center was physically open (PO) were compared to one interval when the center was physically closed (PC) (all evaluations were conducted via direct-to-home TNP) and a fourth interval when the center was physically reopened (RO) and evaluations were conducted in one of the three modalities: in-person, virtual only or hybrid (both virtual/in-person). RESULTS: A total of 1,459 total neuropsychological evaluations were conducted with a 64.6% reduction during PC. At RO, the number of evaluations returned to pre-COVID baseline during which in-person (72.4%) evaluations were conducted at a higher rate than hybrid (7.1%) or virtual only (20.4%). Across the lifespan, mean number of appointments to complete evaluations was significantly greater during PC (p< .001) than at other time intervals, and during RO, hybrid evaluations required significantly more appointments (p < .001) than in-person and virtual. The majority of evaluations were conducted with adult patients (71.4%). For adult patients, neurodegenerative/memory disorders received TNP evaluations at a higher rate during PC and RO. Pediatric patients were significantly older during PC (p < .001); neurodevelopmental referrals received more hybrid and virtual evaluations. CONCLUSIONS: Results indicate that patient characteristics, especially age and referral categories, impact the feasibility of TNP. Data from the RO period suggest that in-person evaluations not surprisingly remain the mainstay; however, for adult patients, and especially older adults with neurodegenerative/memory disorders, TNP may provide an important option for delivery of neuropsychological evaluations.

Intellectual functioning among case-matched cohorts of children treated with proton or photon radiation for standard-risk medulloblastoma.

BACKGROUND: Proton therapy may reduce cognitive deficits after radiotherapy among brain tumor survivors, although current data are limited to retrospective comparisons between historical cohorts. The authors compared intelligence quotient scores within a case-matched cohort of children with medulloblastoma treated with proton radiation (PRT) or photon radiation (XRT) over the same time period. METHODS: Among 88 consecutive patients with standard-risk medulloblastoma treated with PRT or XRT at 2 institutions from 2000 to 2009, 50 were matched 1:1 (25 with PRT and 25 with XRT) according to age, gender, date of diagnosis, histology, radiation boost, and craniospinal irradiation dose. One-way analyses of variance were performed to compare the Full-Scale Intelligence Quotient (FSIQ) and associated index scores between the 2 cohorts. RESULTS: Neurocognitive data were available for 37 survivors (17 with PRT and 20 with XRT) from the matched cohort. The mean age was 8.5 years (SD, 4.14 years). The median follow-up was 5.3 years (range, 1.0-11.4 years) and 4.6 years (range, 1.1-11.2 years) for the PRT and XRT cohorts, respectively (P = .193). Patients treated with PRT had significantly higher mean FSIQ (99.6 vs 86.2; P = .021), verbal (105.2 vs 88.6; P = .010), and nonverbal scores (103.1 vs 88.9; P = .011) than the XRT-treated cohort. Differences in processing speed (82.9 vs 77.2; P = .331) and working memory (97.0 vs 92.7; P = .388) were not statistically significant. CONCLUSIONS: Radiotherapy-associated cognitive effects appear to be more attenuated after proton therapy. Comprehensive prospective studies are needed to appropriately evaluate the neurocognitive advantages of proton therapy.

Cross-Sectional Exploration of Plasma Biomarkers of Alzheimer's Disease in Down Syndrome: Early Data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study.

With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer's disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid ß peptides (Aß1-40, Aß1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology.

Clinical outcomes of pediatric patients with autism spectrum disorder and other neurodevelopmental disorders and intracranial germ cell tumors.

INTRODUCTION: Intracranial germ cell tumors (IGCTs) are rare tumors of the central nervous system with peak incidence around puberty. Given the developmental origins of IGCTs, we investigated the prevalence of neurodevelopmental disorders (NDDs) in patients with IGCTs and characterized outcomes for patients with NDD and IGCTs. METHODS: A retrospective review of medical records was conducted for 111 patients diagnosed with IGCTs between 1998 and 2018 and evaluated at the Massachusetts General Hospital. Kaplan-Meier method and log-rank test was used for survival analyses. Cox regression analyses were performed for parameters associated with progression-free survival (PFS). RESULTS: Median age at IGCT diagnosis was 12.8 years (range: 4.3-21.7) and median follow-up was 6.5 years (range: 0.2-20.5). Eighteen patients were diagnosed with NDDs prior to IGCT diagnosis, including five patients with autism spectrum disorder (ASD). Of the 67 patients with pure germinomas, four (6.0 %) had prior ASD diagnoses. Patients with NDD had significantly inferior PFS in the nongerminomatous germ cell tumor (NGGCT) cohort. On univariate and multivariable analyses, craniospinal irradiation (CSI) was significantly associated with improved PFS in the NGGCT cohort. CONCLUSIONS: Our study found an ASD prevalence in the pure germinoma cohort more than threefold greater than the national prevalence, suggesting an association between ASD and pure germinomas. Furthermore, patients with NDD and NGGCT had worse PFS, possibly due to fewer patients with NDD receiving CSI. Future prospective studies with larger cohorts are needed to examine associations between NDDs and IGCTs, and further characterize outcomes for patients with NDDs and IGCTs.

Redefining Success by Focusing on Failures After Pediatric Hypoglossal Stimulation in Down Syndrome.

OBJECTIVES/HYPOTHESIS: Patients with Down syndrome have a high incidence of obstructive sleep apnea (OSA) and limited treatment options. Hypoglossal stimulation has shown efficacy but has not yet been approved for pediatric populations. Our objective is to characterize the therapy response of adolescent patients with down syndrome and severe OSA who underwent hypoglossal stimulation. STUDY DESIGN: Prospective longitudinal trial. METHODS: We are conducting a multicenter single-arm trial of hypoglossal stimulation for adolescent patients with Down syndrome and severe OSA. Interim analysis was performed to compare objective sleep and quality of life outcomes at 12 months postoperatively for the first 20 patients. RESULTS: The mean age was 15.5 and baseline AHI 24.2. Of the 20 patients, two patients (10.0%) had an AHI under 1.5 at 12 months; nine patients of 20 (45.0%) under five; and 15 patients of 20 (75.0%) under 10. The mean decrease in AHI was 15.1 (P < .001). Patients with postoperative AHI over five had an average baseline OSA-18 survey score of 3.5 with an average improvement of 1.7 (P = .002); in addition, six of these patients had a relative decrease of apneas compared to hypopneas and seven had an improvement in percentage of time with oxygen saturation below 90%. CONCLUSIONS: Patients with persistently elevated AHI 12 months after hypoglossal implantation experienced improvement in polysomnographic and quality of life outcomes. These results suggest the need for a closer look at physiologic markers for success beyond reporting AHI as the gold standard. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1663-1669, 2021.

Language skills as a predictor of cognitive decline in adults with Down syndrome.

INTRODUCTION: Adults with Down syndrome (DS) are at high risk for early onset Alzheimer's disease (AD), characterized by a progressive decline in multiple cognitive domains including language, which can impact social interactions, behavior, and quality of life. This cross-sectional study examined the relationship between language skills and dementia. METHODS: A total of 168 adults with DS (mean age = 51.4 years) received neuropsychological assessments, including Vineland Communication Domain, McCarthy Verbal Fluency, and Boston Naming Test, and were categorized in one of three clinical groups: cognitively stable (CS, 57.8%); mild cognitive impairment (MCI-DS, 22.6%); and probable/definite dementia (AD-DS, 19.6%). Logistic regression was used to determine how well language measures predict group status. RESULTS: Vineland Communication, particularly receptive language, was a significant predictor of MCI-DS. Semantic verbal fluency was the strongest predictor of AD-DS. DISCUSSION: Assessment of language skills can aid in the identification of dementia in adults with DS. Clinically, indications of emerging language problems should warrant further evaluation and monitoring.

A comparison study assessing neuropsychological outcome of patients with post-operative pediatric cerebellar mutism syndrome and matched controls after proton radiation therapy.

PURPOSE: Post-operative pediatric cerebellar mutism syndrome (CMS), characterized by mutism, ataxia/hypotonia, and emotional lability, can result in long-term deficits following resection of posterior fossa (PF) tumors. This longitudinal study compared neuropsychological outcomes of pediatric patients with post-operative CMS to a matched control patient group without CMS. METHODS: Fifty-eight PF tumor patients received post-surgical proton radiation therapy (PRT) and testing at baseline and at ≥ 1-year post-PRT over a 10-year period. Of these, 18 (31%) had post-operative CMS with baseline and follow-up neuropsychological test data. Those participants were matched to 18 controls by tumor location, age, gender, and handedness; no significant group differences were found at baseline for clinical/demographic variables. Total mean age at baseline was 7.26 years (SD = 4.42); mean follow-up interval was 3.26 years (SD = 2.24). Areas assessed: overall intelligence, expressive and receptive vocabulary, visuomotor integration, fine motor speed, inhibition, emotional control, depression, and anxiety. RESULTS: Patients were 52% male; 86% medulloblastoma/14% ependymoma; 86% craniospinal irradiation/14% focal radiation; and 86% chemotherapy. No group differences were found between most mean baseline scores; expressive vocabulary and fine motor speed were significantly lower in the post-operative CMS group (p < 0.05). Mean change scores revealed no significant differences for the sample; scores were within the normal range except fine motor skills were impaired for both groups. CONCLUSIONS: Longitudinal neuropsychological outcomes for post-operative pediatric CMS patients did not differ significantly from matched controls without this condition. Patients were in the normal range in all areas except fine motor speed, which was impaired for both groups independent of CMS diagnosis.

Pediatric postoperative cerebellar cognitive affective syndrome follows outflow pathway lesions.

OBJECTIVE: To evaluate lesion location after pediatric cerebellar tumor resection in relation to the development of severe cognitive and affective disturbances, or cerebellar cognitive affective syndrome (CCAS). METHODS: The postsurgical lesion location of 195 pediatric patients with cerebellar tumors was mapped onto a template brain. Individuals with CCAS were matched to 2 participants without CCAS by sex, age, and lesion volume. Lesion analyses included both a hypothesis-driven evaluation of the cerebellar outflow pathway (deep nuclei and superior cerebellar peduncles) and data-driven multivariate lesion symptom mapping. Lesion-associated networks were evaluated by comparing connectivity patterns between the lesion location of cases with and those without CCAS with resting-state functional connectivity MRI data from large normative adult and pediatric cohorts. RESULTS: CCAS was present in 48 of 195 participants (24.6%) and was strongly associated with cerebellar outflow tract lesions (p < 0.0001). Lesion symptom mapping also highlighted the cerebellar outflow pathway, with peak findings in the fastigial nuclei extending into the inferior vermis. Lesion network mapping revealed that the cerebellar region most associated with CCAS was functionally connected to the thalamic mediodorsal nucleus, among other sites, and that higher connectivity between lesion location and the mediodorsal nucleus predicts CCAS occurrence (p < 0.01). A secondary analysis of 27 participants with mutism revealed similar localization of lesions and lesion-associated networks. CONCLUSION: Lesions of the cerebellar outflow pathway and inferior vermis are associated with major cognitive and affective disturbances after pediatric cerebellar tumor resection, and disrupted communication between the cerebellum and the thalamic mediodorsal nucleus may be important.

Cognitive and Adaptive Outcomes After Proton Radiation for Pediatric Patients With Brain Tumors.

PURPOSE: Radiation therapy is integral in treatment of pediatric brain tumors, but it is associated with negative long-term sequelae. Proton beam radiation therapy (PRT), which enables better focusing of radiation on tumors, may entail fewer sequelae. This prospective study examined cognitive and adaptive functioning in children and young adults treated with PRT. METHODS AND MATERIALS: A total of 155 patients were assessed using age-appropriate measures for cognitive and adaptive functioning at start of or during PRT (baseline) and at follow-up. Mean age at baseline was 8.9 years; mean follow-up interval was 3.6 years. Diagnoses included medulloblastoma, craniopharyngioma, ependymoma, glial tumors, germ cell tumors, and others. The sample was divided by age at baseline (<6 years [N = 57, or 37%] and ≥6 years [N = 98, or 63%]) and by PRT field (craniospinal irradiation [CSI; 39%] and focal irradiation [61%]). RESULTS: Scores for mean intelligence quotient (IQ) and adaptive functioning skills were in the average range at baseline and follow-up. Overall, mean IQ scores declined from 105.4 to 102.5 (P = .005); however, only the younger CSI group showed significant decline. Patients receiving CSI, regardless of age, appeared particularly vulnerable in IQ, processing speed, and working memory. Adaptive skills were stable across the 4 age-by-treatment field groups. CONCLUSIONS: At a mean of 3.6 years after PRT, IQ declined slightly for the group, largely because of significant IQ decline in younger patients treated with CSI. No significant change was seen in patients <6 years treated with focal PRT or in older patients. Adaptive skills remained stable across age and treatment type.

Estimated IQ Systematically Underestimates Neurocognitive Sequelae in Irradiated Pediatric Brain Tumor Survivors.

PURPOSE: While cranial irradiation is often essential to attain a cure for pediatric brain tumors, it is associated with adverse neurocognitive outcomes, primarily manifested as declines in full-scale IQ (FSIQ). This decline results primarily from a decline in processing speed, a component of FSIQ. However, estimated IQ (EIQ) is frequently used in research and clinical settings but does not incorporate processing speed. We hypothesized that EIQ systematically underestimates neurocognitive sequelae in irradiated pediatric brain tumor survivors. METHODS AND MATERIALS: We treated 185 pediatric brain tumor patients with proton radiation therapy. All patients had at least 1 neuropsychological evaluation at baseline and/or 1 or more follow-up evaluations with sufficient data to calculate both FSIQ and EIQ. The Wechsler Intelligence Scales were used to calculate FSIQ and EIQ for each patient, and mixed linear models were used to assess disparities between FSIQ and EIQ. RESULTS: At baseline, EIQ was 2.2 points (95% confidence interval 1.2-3.2 points) higher on average than FSIQ (P < .001). The median follow-up period was 26 months. The disparity between EIQ and FSIQ persisted and worsened over time (P = .012), with FSIQ losing on average 0.4 points/year (95% confidence interval 0.01-0.8 points/year) relative to EIQ. The disparity at baseline varied with sex and age. CONCLUSIONS: EIQ systematically underestimates the neurocognitive sequelae of children treated with cranial radiation therapy. FSIQ is much more likely than EIQ to identify neurocognitive deficits, allowing for appropriate interventions, as well as academic services and accommodations. Thus, EIQ should have a very limited role in both clinical and research settings for this population.

Quality of life in patients with proton-treated pediatric medulloblastoma: Results of a prospective assessment with 5-year follow-up.

BACKGROUND: To the authors' knowledge, health-related quality of life (HRQOL) outcomes are not well described in patients with medulloblastoma. The use of proton radiotherapy (RT) may translate into an improved HRQOL. In the current study, the authors report long-term HRQOL in patients with proton-treated pediatric medulloblastoma. METHODS: The current study was a prospective cohort HRQOL study of patients with medulloblastoma who were treated with proton RT and enrolled between August 5, 2002, and October 8, 2015. Both child report and parent-proxy report Pediatric Quality of Life Inventory (PedsQL) surveys were collected at baseline during RT and annually thereafter (score range on surveys of 0-100, with higher scores indicating better HRQOL). Patients were dichotomized by clinical/treatment variables and subgroups were compared. Mixed-model analysis was performed to determine the longitudinal trajectory of PedsQL scores. The Student t test was used to compare long-term HRQOL measures with published means from a healthy child population. RESULTS: Survey data were evaluable for 116 patients with a median follow-up of 5 years (range, 1-10.6 years); the median age at the time of diagnosis was 7.6 years (range, 2.1-18.1 years). At baseline, children reported a total core score (TCS) of 65.9, which increased by 1.8 points annually (P<.001); parents reported a TCS of 59.1, which increased by 2.0 points annually. Posterior fossa syndrome adversely affected baseline scores, but these scores significantly improved with time. At the time of last follow-up, children reported a TCS of 76.3, which was 3.3 points lower than that of healthy children (P = .09); parents reported a TCS of 69, which was 11.9 points lower than that of parents of healthy children (P<.001). Increased follow-up time from diagnosis correlated with improved HRQOL scores. CONCLUSIONS: HRQOL scores appear to increase over time after treatment in children treated with proton RT for medulloblastoma but remain lower compared with those of parent-proxy reports as well as published means from a healthy normative sample of children. Additional follow-up may translate into continued improvements in HRQOL. Cancer 2018. © 2018 American Cancer Society.

Left hippocampal dosimetry correlates with visual and verbal memory outcomes in survivors of pediatric brain tumors.

BACKGROUND: Radiotherapy (RT) in the pediatric brain tumor population causes late neurocognitive effects. In the current study, the authors investigated associations between clinical and dosimetric risk factors and memory outcomes in a cohort of patients treated with proton radiotherapy (PRT). METHODS: A total of 70 patients (median age at PRT, 12.1 years [range, 5.0-22.5 years]) who were treated with PRT were identified with baseline and follow-up evaluations of visual and verbal memory (Children's Memory Scale and the third edition of the Wechsler Memory Scale). Whole-brain as well as bilateral hippocampal and temporal lobe contours were delineated for the calculation of dosimetric indices. Multivariate analyses were performed to assess associations of score changes over time with clinical factors and dosimetric indices. RESULTS: The median neurocognitive follow-up was 3.0 years (range, 1.1-11.4 years). For the entire cohort, delayed and immediate verbal memory scaled scores demonstrated small declines. The mean decline for delayed verbal memory scores was 0.6 (P = .01), and that for immediate verbal memory scores was 0.5 (P = .06). Immediate and delayed visual memory scores were not found to change significantly (+0.1 and -0.3, respectively; P>.30). A higher left hippocampal V20GyE (percentage of the volume of a particular anatomical region receiving at least a 20 gray equivalent) was correlated with a score decline in all 4 measures. Female sex was found to be predictive of lower delayed verbal memory follow-up scores (P = .035). CONCLUSIONS: Only delayed verbal memory scores were found to have declined statistically significantly at follow-up after PRT, reflecting some weakness in verbal memory retrieval. Given a correlation of left hippocampal dosimetry and memory outcomes after PRT, left hippocampal-sparing PRT plans may assist patients with pediatric brain tumors in preserving memory-retrieval abilities. Cancer 2018;124:2238-45. © 2018 American Cancer Society.

Executive functioning, academic skills, and quality of life in pediatric patients with brain tumors post-proton radiation therapy.

Radiation therapy (RT) is integral in the treatment of pediatric brain tumors; however, photon RT (XRT) often results in intellectual decline, executive functioning (EF) deficits, academic underachievement/failure, and lower health-related quality of life (HRQoL). Proton RT (PRT) provides more targeted therapy, minimizing damage to the developing brain, yet few studies have examined its neuropsychological effects. This study investigated the role of EF in academic skills and HRQoL in a sample of children treated with PRT. A mediation model was proposed in which academic skills mediated relations between aspects of EF and school-based HRQoL (sHRQoL). Sixty-five children (x̅age = 12.4; 43.9% male) treated with PRT completed follow-up neuropsychological testing as part of routine care. Measures included assessment of intellectual functioning, EF, attention, and academic skills (reading, math, spelling). Parents reported on children's EF and attention problems. sHRQoL was assessed via child self-report. Children who underwent PRT demonstrated relatively intact intelligence, academics, attention, EF, and sHRQoL, but were at risk for reduced processing speed. Poorer working memory and processing speed were related to lower sHRQoL. Better EF and faster processing speed were associated with better academic skills, which were linked to higher sHRQoL. Better working memory was associated with better math performance, which was linked to higher sHRQoL; this relationship did not hold for reading or spelling. Results highlight the importance of EF skills in academic performance and sHRQoL, and the need for routine screening of EF deficits and proactive supports. Supports may include cognitive rehabilitation and in-class accommodations. Overall, results compare favorably to XRT outcomes reported in the literature.

Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study.

BACKGROUND: Compared with traditional photon radiotherapy, proton radiotherapy irradiates less normal tissue and might improve health outcomes associated with photon radiotherapy by reducing toxic effects to normal tissue. We did a trial to assess late complications, acute side-effects, and survival associated with proton radiotherapy in children with medulloblastoma. METHODS: In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients aged 3-21 years who had medulloblastoma. Patients had craniospinal irradiation of 18-36 Gy radiobiological equivalents (GyRBE) delivered at 1·8 GyRBE per fraction followed by a boost dose. The primary outcome was cumulative incidence of ototoxicity at 3 years, graded with the Pediatric Oncology Group ototoxicity scale (0-4), in the intention-to-treat population. Secondary outcomes were neuroendocrine toxic effects and neurocognitive toxic effects, assessed by intention-to-treat. This study is registered at ClinicalTrials.gov, number NCT00105560. FINDINGS: We enrolled 59 patients from May 20, 2003, to Dec 10, 2009: 39 with standard-risk disease, six with intermediate-risk disease, and 14 with high-risk disease. 59 patients received chemotherapy. Median follow-up of survivors was 7·0 years (IQR 5·2-8·6). All patients received the intended doses of proton radiotherapy. The median craniospinal irradiation dose was 23·4 GyRBE (IQR 23·4-27·0) and median boost dose was 54·0 GyRBE (IQR 54·0-54·0). Four (9%) of 45 evaluable patients had grade 3-4 ototoxicity according to Pediatric Oncology Group ototoxicity scale in both ears at follow-up, and three (7%) of 45 patients developed grade 3-4 ototoxicity in one ear, although one later reverted to grade 2. The cumulative incidence of grade 3-4 hearing loss at 3 years was 12% (95% CI 4-25). At 5 years, it was 16% (95% CI 6-29). Pediatric Oncology Group hearing ototoxicity score at a follow-up of 5·0 years (IQR 2·9-6·4) was the same as at baseline or improved by 1 point in 34 (35%) of 98 ears, worsened by 1 point in 21 (21%), worsened by 2 points in 35 (36%), worsened by 3 points in six (6%), and worsened by 4 points in two (2%). Full Scale Intelligence Quotient decreased by 1·5 points (95% CI 0·9-2·1) per year after median follow-up up of 5·2 years (IQR 2·6-6·4), driven by decrements in processing speed and verbal comprehension index. Perceptual reasoning index and working memory did not change significantly. Cumulative incidence of any neuroendocrine deficit at 5 years was 55% (95% CI 41-67), with growth hormone deficit being most common. We recorded no cardiac, pulmonary, or gastrointestinal late toxic effects. 3-year progression-free survival was 83% (95% CI 71-90) for all patients. In post-hoc analyses, 5-year progression-free survival was 80% (95% CI 67-88) and 5-year overall survival was 83% (95% CI 70-90). INTERPRETATION: Proton radiotherapy resulted in acceptable toxicity and had similar survival outcomes to those noted with conventional radiotherapy, suggesting that the use of the treatment may be an alternative to photon-based treatments. FUNDING: US National Cancer Institute and Massachusetts General Hospital.