Neurodegenerative disease pathways are perturbed in patients with cancer who self-report cognitive changes and anxiety: A pathway impact analysis.

BACKGROUND: Cancer-related cognitive impairment (CRCI) and anxiety co-occur in patients with cancer. Little is known about mechanisms for the co-occurrence of these two symptoms. The purposes of this secondary analysis were to evaluate for perturbed pathways associated with the co-occurrence of self-reported CRCI and anxiety in patients with low versus high levels of these two symptoms and to identify potential mechanisms for the co-occurrence of CRCI and anxiety using biological processes common across any perturbed neurodegenerative disease pathways. METHODS: Patients completed the Attentional Function Index and the Spielberger State-Trait Anxiety Inventory six times over two cycles of chemotherapy. Based on findings from a previous latent profile analysis, patients were grouped into none versus both high levels of these symptoms. Gene expression was quantified, and pathway impact analyses were performed. Signaling pathways for evaluation were defined with the Kyoto Encyclopedia of Genes and Genomes database. RESULTS: A total of 451 patients had data available for analysis. Approximately 85.0% of patients were in the none class and 15.0% were in the both high class. Pathway impact analyses identified five perturbed pathways related to neurodegenerative diseases (i.e., amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, prion disease, and pathways of neurodegeneration-multiple diseases). Apoptosis, mitochondrial dysfunction, oxidative stress, and endoplasmic reticulum stress were common biological processes across these pathways. CONCLUSIONS: This study is the first to describe perturbations in neurodegenerative disease pathways associated with CRCI and anxiety in patients receiving chemotherapy. These findings provide new insights into potential targets for the development of mechanistically based interventions.

Virtual multi-institutional tumor board: a strategy for personalized diagnoses and management of rare CNS tumors.

PURPOSE: Multidisciplinary tumor boards (MTBs) integrate clinical, molecular, and radiological information and facilitate coordination of neuro-oncology care. During the COVID-19 pandemic, our MTB transitioned to a virtual and multi-institutional format. We hypothesized that this expansion would allow expert review of challenging neuro-oncology cases and contribute to the care of patients with limited access to specialized centers. METHODS: We retrospectively reviewed records from virtual MTBs held between 04/2020-03/2021. Data collected included measures of potential clinical impact, including referrals to observational or therapeutic studies, referrals for specialized neuropathology analysis, and whether molecular findings led to a change in diagnosis and/or guided management suggestions. RESULTS: During 25 meetings, 32 presenters discussed 44 cases. Approximately half (n = 20; 48%) involved a rare central nervous system (CNS) tumor. In 21% (n = 9) the diagnosis was changed or refined based on molecular profiling obtained at the NIH and in 36% (n = 15) molecular findings guided management. Clinical trial suggestions were offered to 31% (n = 13), enrollment in the observational NCI Natural History Study to 21% (n = 9), neuropathology review and molecular testing at the NIH to 17% (n = 7), and all received management suggestions. CONCLUSION: Virtual multi-institutional MTBs enable remote expert review of CNS tumors. We propose them as a strategy to facilitate expert opinions from specialized centers, especially for rare CNS tumors, helping mitigate geographic barriers to patient care and serving as a pre-screening tool for studies. Advanced molecular testing is key to obtaining a precise diagnosis, discovering potentially actionable targets, and guiding management.

National Cancer Institute Collaborative Workshop on Shaping the Landscape of Brain Metastases Research: challenges and recommended priorities.

Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes. This Policy Review outlines existing knowledge gaps, collaborative opportunities, and specific recommendations regarding consensus priorities and future directions in brain metastases research. Achieving major advances in research will require enhanced coordination between the ongoing efforts of individual organisations and consortia. Importantly, the continual and active engagement of patients and patient advocates will be necessary to ensure that the directionality of all efforts reflects what is most meaningful in the context of patient care.

Feasibility and preliminary efficacy of a virtual reality intervention targeting distress and anxiety in primary brain tumor patients at the time of clinical evaluation: Study protocol for a phase 2 clinical trial.

BACKGROUND: Primary brain tumor (PBT) patients experience higher levels of distress and anxiety than other solid tumor patients, particularly at the time of clinical evaluation when uncertainty about disease status is high ("scanxiety"). There is promising evidence supporting use of virtual reality (VR) to target psychological symptoms in other solid tumor patients, though PBT patients have not been studied extensively in this context. The primary aim of this phase 2 clinical trial is to establish the feasibility of a remote VR-based relaxation intervention for a PBT population, with secondary aims designed to determine preliminary efficacy of improving distress and anxiety symptoms. METHODS: PBT patients (N = 120) with upcoming MRI scans and clinical appointments who meet eligibility will be recruited to participate in a single arm trial conducted remotely through the NIH. Following completion of baseline assessments, participants will complete a 5-min VR intervention via telehealth using a head-mounted immersive device while under supervision of the research team. Following the intervention, over the course of 1 month patients can use VR at their discretion with follow-up assessments done immediately post-VR intervention, as well as 1 week and 4 weeks later. Additionally, a qualitative phone interview will be conducted to assess patient satisfaction with the intervention. DISCUSSION: Use of immersive VR is an innovative interventional approach to target distress and scanxiety symptoms in PBT patients who are at high risk for experiencing these symptoms leading into their clinical appointments. Findings from this study may inform design of a future multicenter randomized VR trial for PBT patients and may aid in development of similar interventions for other oncology populations. TRIAL REGISTRATION: Clinicaltrials.gov (NCT04301089), registered 9 March 2020.

Identification of health-related quality of life profiles among long-term survivors of primary central nervous system tumors.

PURPOSE: We aimed to identify health-related quality of life (HRQOL) latent classes among primary central nervous system tumor (PCNST) long-term survivors (LTS) and to evaluate differences between classes in survivor sociodemographic characteristics, clinical characteristics, and symptoms to guide  the development of survivorship care programs tailored to unique class needs. METHODS: Data from 298 PCNST LTS reporting HRQOL on the EQ-5D-3L were analyzed using latent profile analysis. Correlations and independent group t-tests were performed to identify differences between identified HRQOL classes by sociodemographic, clinical characteristics, and symptoms. RESULTS: Sample mean age was 48 years, 54% were male, 82% Caucasian, 56% employed, 60% had a high-grade glioma, and 52% had a KPS ≥ 90. Two HRQOL classes, good (61%) and poor (39%), were identified. The good HRQOL class reported no problems with self-care and few problems with mobility or usual activities. Thirty-eight percent reported anxiety and depression and 21% pain. Over 94% of the poor HRQOL class had at least moderate problems with mobility and usual activities, and over 50% had pain, self-care issues, anxiety, and depression. Older age (φ = 0.21), unemployment (φ = 0.30), spine tumors (φ = 0.18), active treatment (φ = 0.20), tumor recurrence (φ = 0.28), and poorer KPS scores (φ = 0.61) were associated with membership in the poor HRQOL class. CONCLUSIONS: In the poor PCNST LTS HRQOL class, an overwhelming majority faced significant physical challenges, and the good HRQOL class experienced mood-related disturbance but limited physical challenges. These HRQOL profiles can be used to guide survivorship programs and tailored interventions.

Capturing evolving definitions of 12 select rare CNS tumors: a timely report from CBTRUS and NCI-CONNECT.

PURPOSE: Incidence, prevalence, and survival are population-based statistics describing cancer burden. The National Cancer Institute's (NCI) Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) specializes in tumor biology and outcomes for 12 rare CNS tumor types selected for their importance in adults, research interest, or potential for targeted treatment. The aim of this study was to update incidence, prevalence, and survival statistics for these tumors. METHODS: The Central Brain Tumor Registry of the United States (CBTRUS) database, a combined dataset of Centers for Disease Control and Prevention's (CDC) National Program of Cancer Registries (NPCR) and NCI's Surveillance, Epidemiology and End Results (SEER) data, was used to calculate average annual age-adjusted incidence rates (AAAIR) per 100,000 population overall and by sex, race-ethnicity, and age for diagnosis years 2008-2019. Incidence time trends were calculated for diagnosis years 2004-2019. NPCR data were used to calculate relative survival rates. Point prevalence on December 31, 2019 was estimated using annual age-specific incidence and survival. RESULTS: AAAIR was 1.47 per 100,000 for these tumors combined, with highest incidence in ependymomas (AAAIR = 0.41/100,000). Most tumor types were more common in males, adults (ages 40 + years) or children (ages < 15 years), and non-Hispanic White individuals. Ependymomas were the most prevalent tumor type (19,320 cases) followed by oligodendrogliomas (14,900 cases). Ependymomas had the highest five-year survival (90.6%) and primary CNS sarcomas the lowest (7.7%). CONCLUSIONS: These data provide means to measure the impact of clinical care and evaluate new therapies and the evolving histopathology definitions in rare CNS tumor types.

Feasibility of a virtual reality intervention targeting distress and anxiety symptoms in patients with primary brain tumors: Interim analysis of a phase 2 clinical trial.

PURPOSE: Cancer patients experience distress and anxiety when undergoing imaging studies to monitor disease status, yet these symptoms are not always appropriately identified or well-managed. This interim analysis of a phase 2 clinical trial explored feasibility and acceptability of a virtual reality relaxation (VR) intervention for primary brain tumor (PBT) patients at the time of clinical evaluation. METHODS: English speaking, adult PBT patients with previous reports of distress and upcoming neuroimaging were recruited between March of 2021 and March 2022. A brief VR session was done within 2 weeks prior to neuroimaging with patient-reported outcomes (PROs) collected before and immediately post-intervention. Self-directed VR use over the next 1 month was encouraged with additional PROs assessments at 1 and 4 weeks. Feasibility metrics included enrollment, eligibility, attrition, and device-related adverse effects with satisfaction measured with qualitative phone interviews. RESULTS: Fifty-five patients were approached via email, 40 (73%) responded and 20 (50%) enrolled (9 declines, 11 screen fails). 65% of participants were ≤ 50 years, 50% were male, 90% were White/non-Hispanic, 85% had good KPS (≥ 90), and most were on active treatment. All patients completed the VR intervention, PROs questionnaires, weekly check-ins, and qualitative interview. Most (90%) reported frequent VR use and high satisfaction and only 7 mild AEs were recorded (headache, dizziness, nausea, neck pain). CONCLUSION: This interim analysis supports feasibility and acceptability of a novel VR intervention to target psychological symptoms for PBT patients. Trial enrollment will continue to assess for intervention efficacy. TRIAL REGISTRATION: NCT04301089 registered on 3/9/2020.

An Evaluation of the Multifactorial Model of Cancer-Related Cognitive Impairment.

BACKGROUND: Up to 45% of patients report cancer-related cognitive impairment (CRCI). A variety of characteristics are associated with the occurrence and/or severity of CRCI. However, an important gap in knowledge of risk factors for CRCI is the relative contribution of each factor. The multifactorial model of cancer-related cognitive impairment (MMCRCI) is a conceptual model of CRCI that can be used to evaluate the strength of relationships between various factors and CRCI. OBJECTIVES: The purpose of this study was to use structural regression methods to evaluate the MMCRCI using data from a large sample of outpatients receiving chemotherapy ( n = 1,343). Specifically, the relationships between self-reported CRCI and four MMCRCI concepts (i.e., social determinants of health, patient-specific factors, treatment factors, and co-occurring symptoms) were examined. The goals were to determine how well the four concepts predicted CRCI and determine the relative contribution of each concept to deficits in perceived cognitive function. METHODS: This study is part of a larger, longitudinal study that evaluated the symptom experience of oncology outpatients receiving chemotherapy. Adult patients were diagnosed with breast, gastrointestinal, gynecological, or lung cancer; had received chemotherapy within the preceding 4 weeks; were scheduled to receive at least two additional cycles of chemotherapy; were able to read, write, and understand English; and gave written informed consent. Self-reported CRCI was assessed using the attentional function index. Available study data were used to define the latent variables. RESULTS: On average, patients were 57 years of age, college educated, and with a mean Karnofsky Performance Status score of 80. Of the four concepts evaluated, whereas co-occurring symptoms explained the largest amount of variance in CRCI, treatment factors explained the smallest amount of variance. A simultaneous structural regression model that estimated the joint effect of the four exogenous latent variables on the CRCI latent variable was not significant. DISCUSSION: These findings suggest that testing individual components of the MMCRCI may provide useful information on the relationships among various risk factors, as well as refinements of the model. In terms of risk factors for CRCI, co-occurring symptoms may be more significant than treatment factors, patient-specific factors, and/or social determinants of health in patients receiving chemotherapy.

High-grade glioma with pleomorphic and pseudopapillary features (HPAP): a proposed type of circumscribed glioma in adults harboring frequent TP53 mutations and recurrent monosomy 13.

Tumors of the central nervous system (CNS) often display a wide morphologic spectrum that has, until recently, been the sole basis for tumor classification. The introduction of the integrated histomolecular diagnostic approach in CNS tumors has facilitated a classification system that is increasingly data-driven and with improved alignment to clinical outcome. Here, we report a previously uncharacterized glioma type (n = 31) using unsupervised clustering analysis of DNA methylation array data from approximately 14,000 CNS tumor samples. Histologic examination revealed circumscribed growth and morphologic similarities to pleomorphic xanthoastrocytoma (PXA), astroblastoma, ependymoma, polymorphous neuroepithelial tumor of the young (PLNTY), and IDH-wildtype glioblastoma (GBM). Median age (46.5 years) was significantly older than other circumscribed gliomas and younger than GBM. Dimensionality reduction with uniform manifold approximation and projection (UMAP) and hierarchical clustering confirmed a methylation signature distinct from known tumor types and methylation classes. DNA sequencing revealed recurrent mutations in TP53 (57%), RB1 (26%), NF1 (26%), and NF2 (14%). BRAF V600E mutations were detected in 3/27 sequenced cases (12%). Copy number analysis showed increased whole chromosome aneuploidy with recurrent loss of chromosome 13 (28/31 cases, 90%). CDKN2A/B deletion (2/31, 6%) and MGMT promoter methylation (1/31, 3%) were notably rare events. Most tumors showed features of a high-grade glioma, yet survival data showed significantly better overall survival compared to GBM (p < 0.0001). In summary, we describe a previously uncharacterized glioma of adults identified by a distinct DNA methylation signature and recurrent loss of chromosome 13.

Diagnosis and Management of Stroke in Adults with Primary Brain Tumor.

PURPOSE OF REVIEW: This article reviews the risk factors, clinical presentations, differential diagnosis, and the types of strokes frequently seen in patients with primary brain neoplasms. This includes a discussion of approaches with a review of the available literature and provides recommendations for primary and secondary prevention specific to this patient population. RECENT FINDINGS: Strokes in patients with brain tumors are often multifactorial. However, tailored approaches to stroke care are necessary to achieve optimal patient outcomes, AHA/ASA stroke guidelines provide little information on the management of stroke in cancer patients. A comprehensive algorithm for diagnosis for stroke in primary CNS tumor patients is proposed. Understanding the potential complex etiology of stroke in patients with brain tumors is essential to provide appropriate treatment and initiate optimal prevention measures early in the cancer treatment program. Optimal care therefore requires a comprehensive approach including a variety of specialists and healthcare providers.

The effects of SmartCare© on neuro-oncology family caregivers' distress: a randomized controlled trial.

PURPOSE: Patients with primary malignant brain tumors have high symptom burden and commonly rely on family caregivers for practical and emotional support. This can lead to negative mental and physical consequences for caregivers. We investigated effectiveness of an 8-week nurse-led online needs-based support program (SmartCare©) with and without online self-guided cognitive behavioral therapy (CBT) for depression compared to enhanced care as usual (ECAU) on depressive symptoms, caregiving-specific distress, anxiety, mastery, and burden. METHODS: Family caregivers scoring ≥ 6 on a depressive symptoms inventory were randomized to three groups: ECAU plus self-guided CBT and SmartCare©; ECAU plus SmartCare©; ECAU only. Primary outcomes (depressive symptoms; caregiving-specific distress) and secondary outcomes (anxiety, caregiver mastery, and caregiver burden) were assessed online. Intention to treat (ITT) and per protocol (PP) analyses of covariance corrected for baseline scores were performed for outcomes at 4 months. RESULTS: In total, 120 family caregivers participated. Accrual and CBT engagement were lower than expected, therefore intervention groups were combined (n = 80) and compared to ECAU (n = 40). For depressive symptoms, no statistically significant group differences were found. Caregiving-specific distress decreased in the intervention group compared with ECAU (ITT: p = 0.01, partial ɳ2 = 0.08; PP: p = 0.02, partial ɳ2 = 0.08). A trend towards improvement in mastery for the intervention group compared with ECAU was identified (ITT: p = 0.08, partial ɳ2 = 0.04; PP: p = 0.07, partial ɳ2 = 0.05). CONCLUSIONS: SmartCare©, with or without self-guided CBT, reduced caregiving-specific distress with a trend towards improving mastery. SmartCare© has the potential to improve the lives of families coping with a brain tumor diagnosis. TRIAL REGISTRATION NUMBER: NCT02058745; 10 February 2014.

Nonmalignant meningioma and vestibular schwannoma incidence trends in the United States, 2004-2017.

BACKGROUND: Given concerns about risks associated with the growing use of mobile phones over recent decades, the authors analyzed temporal trends in incidence rates of nonmalignant meningioma and vestibular schwannoma in the United States. METHODS: The incidence of nonmalignant meningioma and vestibular schwannoma among adults in the Surveillance, Epidemiology, and End Results 18 registries during 2004 through 2017 was evaluated according to the method of diagnosis: microscopically (MC) or radiographically confirmed (RGC). Annual percent changes (APCs) and 95% CIs were estimated using log-linear models. RESULTS: Overall meningioma rates (n = 108,043) increased significantly from 2004 to 2009 (APC, 5.4%; 95% CI, 4.4%-6.4%) but subsequently rose at a slower pace through 2017 (APC, 1.0%; 95% CI, 0.6%-1.5%). Rates for MC meningiomas changed little from 2004 to 2017 (APC, -0.3%; 95% CI, -0.7%, 0.1%) but rose rapidly for RGC meningiomas until 2009 (APC, 9.5%; 95% CI, 7.8%-11.1%) and rose more modestly thereafter (APC, 2.3%; 95% CI, 1.5%-3.0%). Overall vestibular schwannoma rates (n = 17,475) were stable (APC, 0.4%; 95% CI, -0.2%, 1.0%), but MC vestibular schwannoma rates decreased (APC, -1.9%; 95% CI, -2.7%, -1.1%), whereas RGC vestibular schwannoma rates rose (2006-2017: APC, 1.7%; 95% CI, 0.5%-3.0%). For each tumor, the trends by diagnostic method were similar for each sex and each racial/ethnic group, but RGC diagnosis was more likely in older patients and for smaller tumors. Meningioma trends and the proportion of RGC diagnoses varied notably by registry. CONCLUSIONS: Overall trends obscured differences by diagnostic method in this first large, detailed assessment, but the recent stable rates argue against an association with mobile phone use. Variation among registries requires evaluation to improve the registration of these nonmalignant tumors. LAY SUMMARY: The etiology of most benign meningiomas and vestibular schwannomas is poorly understood, but concerns have been raised about whether mobile phone use contributes to risk of developing these tumors. Descriptive studies examining temporal trends could provide insight; however, globally, few registries collect these nonmalignant cases. In the United States, reporting benign meningiomas and vestibular schwannomas became required by law in 2004. This was the first large, systematic study to quantify and characterize incidence trends for meningioma and vestibular schwannoma according to whether the tumors were diagnosed microscopically or only radiographically. Differential trends across registries and by diagnostic method suggest that caution should be used when interpreting the patterns.

Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors.

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.

Effects of Cognitive Reserve on Cognition in Individuals With Central Nervous System Disease.

Cognitive reserve (CR) has been proposed to account for functional outcome differences in brain pathology and its clinical manifestations. The purpose of our paper is to systematically review the effects of CR on cognitive outcomes in individuals with neurodegenerative and structural CNS diseases. We performed a systematic search of PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and PsychInfo using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Seventeen studies met the predetermined inclusion criteria and were selected for review. Education level was the most commonly used measure for CR, and various neuropsychological tests were used to measure cognitive outcomes. Regardless of the CNS disease of the individuals, almost all of the studies reported a positive association between CR and cognitive outcomes when they were evaluated cross-sectionally. However, when evaluated longitudinally, CR had either no effect on, or a negative association with, cognitive outcomes. Based on studies across a broad spectrum of CNS diseases, our findings suggest that CR may serve as a predictor of cognitive outcomes in individuals with CNS diseases. However, studies to date are limited by a lack of imaging analyses and standardized assessment strategies. The ability to use a standardized measure to assess the longitudinal effects of CR may allow for the development of more targeted treatment methods, resulting in improved disease outcomes for individuals.

Glioma patient-reported outcome assessment in clinical care and research: a Response Assessment in Neuro-Oncology collaborative report.

Clinical trials of treatments for high-grade gliomas have traditionally relied on measures of response or time-dependent metrics; however, these endpoints have limitations because they do not characterise the functional or symptomatic effect of the condition on the person. Including clinical outcome assessments, such as patient- reported outcomes (PROs), to determine net clinical benefit of a treatment strategy is needed because of the substantial burden of symptoms and impaired functioning in this patient population. The US National Cancer Institute convened a meeting to review previous recommendations and existing PRO measures of symptoms and function that can be applied to current trials and clinical practice for high-grade gliomas. Measures were assessed for relevance, relationship to disease and therapy, sensitivity to change, psychometric properties, response format, patient acceptability, and use of self-report. The group also relied on patient input including the results of an online survey, a literature review on available clinical outcomes, expert opinion, and alignment with work done by other organisations. A core set of priority constructs was proposed that allows more comprehensive evaluation of therapies and comparison of outcomes among studies, and enhances efforts to improve the measurement of these core clinical outcomes. The proposed set of constructs was then presented to the Society for Neuro-Oncology Response Assessment in Neuro-Oncology Working Group and feedback was solicited.

Neuroleptic strategies for terminal agitation in patients with cancer and delirium at an acute palliative care unit: a single-centre, double-blind, parallel-group, randomised trial.

BACKGROUND: The role of neuroleptics for terminal agitated delirium is controversial. We assessed the effect of three neuroleptic strategies on refractory agitation in patients with cancer with terminal delirium. METHODS: In this single-centre, double-blind, parallel-group, randomised trial, patients with advanced cancer, aged at least 18 years, admitted to the palliative and supportive care unit at the University of Texas MD Anderson Cancer Center (Houston, TX, USA), with refractory agitation, despite low-dose haloperidol, were randomly assigned to receive intravenous haloperidol dose escalation at 2 mg every 4 h, neuroleptic rotation with chlorpromazine at 25 mg every 4 h, or combined haloperidol at 1 mg and chlorpromazine at 12·5 mg every 4 h, until death or discharge. Rescue doses identical to the scheduled doses were administered at inception, and then hourly as needed. Permuted block randomisation (block size six; 1:1:1) was done, stratified by baseline Richmond Agitation Sedation Scale (RASS) scores. Research staff, clinicians, patients, and caregivers were masked to group assignment. The primary outcome was change in RASS score from time 0 to 24 h. Comparisons among group were done by modified intention-to-treat analysis. This completed study is registered with ClinicalTrials.gov, NCT03021486. FINDINGS: Between July 5, 2017, and July 1, 2019, 998 patients were screened for eligibility, with 68 being enrolled and randomly assigned to treatment; 45 received the masked study interventions (escalation n=15, rotation n=16, combination n=14). RASS score decreased significantly within 30 min and remained low at 24 h in the escalation group (n=10, mean RASS score change between 0 h and 24 h -3·6 [95% CI -5·0 to -2·2]), rotation group (n=11, -3·3 [-4·4 to -2·2]), and combination group (n=10, -3·0 [-4·6 to -1·4]), with no difference among groups (p=0·71). The most common serious toxicity was hypotension (escalation n=6 [40%], rotation n=5 [31%], combination n=3 [21%]); there were no treatment-related deaths. INTERPRETATION: Our data provide preliminary evidence that the three strategies of neuroleptics might reduce agitation in patients with terminal agitation. These findings are in the context of the single-centre design, small sample size, and lack of a placebo-only group. FUNDING: National Institute of Nursing Research.

Proposed Additions to the NCCN Guidelines for Adult Medulloblastoma.

Medulloblastoma is a rare brain tumor that occurs in both children and adults, with patients aged 15 to 39 years accounting for 30% of all cases. In adults, guidelines for diagnosis and treatment are often based on retrospective data and extrapolated from the pediatric experience due to limited availability of prospective trials or registries involving adults. Importantly, adult patients differ from pediatric patients in many aspects, including the molecular features of the tumor and tolerance to treatment. In 2017, the NCI was granted support from the Cancer Moonshot initiative to address the challenges and unmet needs of adults with rare central nervous system (CNS) tumors through the NCI Comprehensive Oncology Network for Evaluating Rare CNS Tumors (NCI-CONNECT). On November 25, 2019, NCI-CONNECT convened a multidisciplinary workshop on adult medulloblastoma. Working groups identified unmet needs in clinical care and research and developed specific action items, including a proposal for inclusion of new items in the NCCN Guidelines for Adult Medulloblastoma, delineated in this review along with the evidence supporting their incorporation. Recommendations included facilitating referral of patients to centers of excellence; promoting patient participation in clinical trials or registries; encouraging use of DNA methylation for confirmation of diagnosis and subgrouping; offering counseling on contraception and fertility preservation; evaluating patients for symptoms and medical management of endocrine, vision, hearing, and neurocognitive deficits; providing psychosocial support and referral to neurorehabilitation; minimizing delays in therapy; and incorporating imaging standards and criteria for progression.

Variations in attitudes towards stereotactic biopsy of adult diffuse midline glioma patients: a survey of members of the AANS/CNS Tumor Section.

PURPOSE: Diffuse midline gliomas are rare midline CNS malignancies that primarily affect children but can also affect adults. While radiation is standard treatment, prognosis remains fatal. Furthermore, due to its sensitive anatomic location, many physicians have been reluctant to perform biopsies without potential for improved prognosis. However, recent advancements in molecular-targeted therapeutics have encouraged greater tissue sampling. While the literature reflects this progress, the landscape of how clinicians actually manage these patients remains unclear. Our goal was to assess the attitudes of current practicing neurosurgical oncologists towards management of adult diffuse midline gliomas, reasons behind their practices, and factors that might influence these practices. METHODS: We created and distributed a survey with 16 multiple choice and open-ended questions to members of the Tumor Section of the Congress of Neurological Surgeons. RESULTS: A total of 81 physicians responded to the survey. Although time since training and volume of glioma patients did not significantly affect the decision to consider clinical trials or to offer biopsy, those that operated on fewer gliomas (< 25/year) were more likely to cite surgical morbidity as the primary reason not to biopsy these midline locations. Further, surgeons with access to more advanced molecular testing were significantly more likely to consider clinical trial eligibility when offering biopsies. CONCLUSION: Factors that affect the management of diffuse midline gliomas and the role of biopsy are relatively uniform across the field, however, there were a few notable differences that reflect the changes within the neuro-oncology field in response to clinical trials.

Temozolomide in secondary prevention of HER2-positive breast cancer brain metastases.

Brain metastases occur in up to 25-55% of patients with metastatic HER2-positive breast cancer. Standard treatment has high rates of recurrence or progression, limiting survival and quality of life in most patients. Temozolomide (TMZ) is known to penetrate the blood-brain barrier and is US FDA approved for treatment of glioblastoma. Our group has demonstrated that low doses of TMZ administered in a prophylactic, metronomic fashion can significantly prevent development of brain metastases in murine models of breast cancer. Based on these findings, we initiated a secondary-prevention clinical trial with oral TMZ given to HER2-positive breast cancer patients with brain metastases after recent local treatment in combination with T-DM1 for systemic control of disease. Primary end point is freedom from new brain metastases at 1 year. (NCT03190967).

Validation study of the Japanese version of MD Anderson Symptom Inventory for Brain Tumor module.

OBJECTIVE: The MD Anderson Symptom Inventory for Brain Tumor (MDASI-BT) module is a widely used instrument for measuring symptom burden and interference of daily activities in brain tumor patients. This study aims to develop and validate its Japanese version (MDASI-BT-Japanese). METHODS: Following forward and backward translation of the original MDASI-BT into Japanese, understandability and feasibility were assessed by cognitive debriefing. Subsequently, patients with brain tumors were asked to fill out MDASI-BT-Japanese and European Quality of Life-5 Dimensions (EQ-5D). Feasibility, reliability and validity of MDASI-BT-Japanese were assessed. RESULTS: Cognitive debriefing confirmed overall ease of completion and good understandability. The study population composed of 140 patients with brain tumors (most commonly gliomas). The mean symptom severity score and mean interference score were 1.9 ± 1.7 and 2.8 ± 2.7, respectively. The top items included distress and drowsiness for symptom severity and general activity and work for interference. The median time required was 4 minutes (range, 0.5-30), and missing values were seen in 1%. Internal consistency was proven by excellent Cronbach's coefficient alpha (0.94 for symptom severity, 0.92 for interference). Test-retest reliability was assessed with acceptable intra-class correlation coefficient (mean, 0.76). Correlation efficient ranged between 0.7 and 0.9 for convergent validity. Known-group validity was confirmed by significantly different mean symptom severity score and mean interference score among patients with different performance status. As evidence of concurrent validity, MDASI-BT-Japanese correlated with EQ-5D in the hypothesized magnitude and direction. CONCLUSIONS: The newly developed MDASI-BT-Japanese has demonstrated feasibility, reliability and validity in evaluation of clinical benefit in Japanese-speaking brain tumor patients.