Potential for Glove Risk Amplification via Direct Physical, Chemical, and Microbiological Contamination.

This review focuses on the potential direct physical, chemical, and microbiological contamination from disposable gloves when utilized in food environments, inclusive of the risks posed to food products as well as worker safety. Unrecognized problems endemic to glove manufacturing were magnified during the COVID-19 pandemic due to high demand, increased focus on PPE performance, availability, supply chain instability, and labor shortages. Multiple evidence-based reports of contamination, toxicity, illness, deaths, and related regulatory action linked to contaminated gloves in food and healthcare have highlighted problems indicative of systemic glove industry shortcomings. The glove manufacturing process was diagramed with sources and pathways of contamination identified, indicating weak points with documented occurrences detailed. Numerous unsafe ingredients can introduce chemical contaminants, potentially posing risks to food and to glove users. Microbial hazards present significant challenges to overall glove safety as contaminants appear to be introduced via polluted water sources or flawed glove manufacturing processes, resulting in increased risks within food and healthcare environments. Frank and opportunistic pathogens along with food spoilage organisms can be introduced to foods and wearers. When the sources and pathways of glove-borne contamination were explored, it was found that physical failures play a pivotal role in the release of sweat build-up, liquefaction of chemical residues, and incubation of microbial contaminants from hands and gloves. Thus, with glove physical integrity issues, including punctures in new, unused gloves that can develop into significant rips and tears, not only can direct physical food contamination occur but also chemical and microbiological contamination can find their way into food. Enhanced regulatory requirements for Acceptable Quality Limits of food-grade gloves, and the establishment of appropriate bioburden standards would enhance safety in food applications. Based on the information provided, together with a false sense of security associated with glove use, the unconditional belief in glove chemical and microbiological purity may be unfounded.

Collection and Analysis of Adherence Information for Software as a Medical Device Clinical Trials: Systematic Review.

BACKGROUND: The rapid growth of digital health apps has necessitated new regulatory approaches to ensure compliance with safety and effectiveness standards. Nonadherence and heterogeneous user engagement with digital health apps can lead to trial estimates that overestimate or underestimate an app's effectiveness. However, there are no current standards for how researchers should measure adherence or address the risk of bias imposed by nonadherence through efficacy analyses. OBJECTIVE: This systematic review aims to address 2 critical questions regarding clinical trials of software as a medical device (SaMD) apps: How well do researchers report adherence and engagement metrics for studies of effectiveness and efficacy? and What efficacy analyses do researchers use to account for nonadherence and how appropriate are their methods? METHODS: We searched the Food and Drug Administration's registration database for registrations of repeated-use, patient-facing SaMD therapeutics. For each such registration, we searched ClinicalTrials.gov, company websites, and MEDLINE for the corresponding clinical trial and study articles through March 2022. Adherence and engagement data were summarized for each of the 24 identified articles, corresponding to 10 SaMD therapeutics. Each article was analyzed with a framework developed using the Cochrane risk-of-bias questions to estimate the potential effects of imperfect adherence on SaMD effectiveness. This review, funded by the Richard King Mellon Foundation, is registered on the Open Science Framework. RESULTS: We found that although most articles (23/24, 96%) reported collecting information about SaMD therapeutic engagement, of the 20 articles for apps with prescribed use, only 9 (45%) reported adherence information across all aspects of prescribed use: 15 (75%) reported metrics for the initiation of therapeutic use, 16 (80%) reported metrics reporting adherence between the initiation and discontinuation of the therapeutic (implementation), and 4 (20%) reported the discontinuation of the therapeutic (persistence). The articles varied in the reported metrics. For trials that reported adherence or engagement, there were 4 definitions of initiation, 8 definitions of implementation, and 4 definitions of persistence. All articles studying a therapeutic with a prescribed use reported effectiveness estimates that might have been affected by nonadherence; only a few (2/20, 10%) used methods appropriate to evaluate efficacy. CONCLUSIONS: This review identifies 5 areas for improving future SaMD trials and studies: use consistent metrics for reporting adherence, use reliable adherence metrics, preregister analyses for observational studies, use less biased efficacy analysis methods, and fully report statistical methods and assumptions.

Phase I trial of panobinostat in children with diffuse intrinsic pontine glioma: A report from the Pediatric Brain Tumor Consortium (PBTC-047).

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood cancer with median survival of less than 1 year. Panobinostat is an oral multihistone deacetylase inhibitor with preclinical activity in DIPG models. Study objectives were to determine safety, tolerability, maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of panobinostat in children with DIPG. PATIENTS AND METHODS: In stratum 1, panobinostat was administered 3 days per week for 3 weeks on, 1 week off to children with progressive DIPG, with dose escalation following a two-stage continual reassessment method. After this MTD was determined, the study was amended to evaluate the MTD in children with nonprogressive DIPG/Diffuse midline glioma (DMG) (stratum 2) on an alternate schedule, 3 days a week every other week in an effort to escalate the dose. RESULTS: For stratum 1, 19 subjects enrolled with 17/19 evaluable for dose-finding. The MTD was 10 mg/m2/dose. Dose-limiting toxicities included thrombocytopenia and neutropenia. Posterior reversible encephalopathy syndrome was reported in 1 patient. For stratum 2, 34 eligible subjects enrolled with 29/34 evaluable for dose finding. The MTD on this schedule was 22 mg/m2/dose. DLTs included thrombocytopenia, neutropenia, neutropenia with grade 4 thrombocytopenia, prolonged intolerable nausea, and increased ALT. CONCLUSIONS: The MTD of panobinostat is 10 mg/m2/dose administered 3 times per week for 3 weeks on/1 week off in children with progressive DIPG/DMG and 22 mg/m2/dose administered 3 times per week for 1 week on/1 week off when administered in a similar population preprogression. The most common toxicity for both schedules was myelosuppression.

Phase II Randomized Trial of Lenalidomide in Children With Pilocytic Astrocytomas and Optic Pathway Gliomas: A Report From the Children's Oncology Group.

PURPOSE: Children with low-grade glioma often require long-term therapy and suffer from treatment morbidity. Although targeted agents are promising, tumor targets often encompass normal developmental pathways and long-term effects of inhibition are unknown. Lenalidomide is an immunomodulatory agent with wide-ranging properties. Phase I studies indicated greater tolerability of lenalidomide in children compared with adults and a potential dose-response effect. PATIENTS AND METHODS: We performed a phase II trial of lenalidomide in children with pilocytic astrocytomas and optic pathway gliomas who failed initial therapy. Primary objectives included determination of objective response rate of children randomly assigned to regimen A, low-dose (20 mg/m2/dose), or regimen B, high-dose (115 mg/m2/dose) lenalidomide, and assessment for early progression. Secondary objectives included estimation of event-free survival, overall survival, incidence of toxic events, and assessment of plasma lenalidomide concentrations. Lenalidomide was administered once daily × 21 days of each 28-day cycle for each regimen. RESULTS: Seventy-four eligible patients were enrolled (n = 37, each arm). The predefined activity level of interest was achieved for both arms. Four objective responses were observed in each arm, and the number of early progressors was low. Eighteen patients completed 26 cycles of therapy (regimen A, n = 12; regimen B, n = 6). The median number of cycles was 14 (range, 2-26) for regimen A and 11 for regimen B (range, 1-26). Of 74 eligible patients who received study drug, 30 required dose reduction for toxicity (regimen A, n = 6; regimen B, n = 24) and 16 discontinued because of toxicity (regimen A, n = 2; regimen B, n = 14). CONCLUSION: Lenalidomide demonstrates a sufficient level of activity in children with low-grade glioma to warrant further exploration. Low-dose (20 mg/m2/dose administered once daily × 21 days of each 28-day cycle) lenalidomide appears to have better tolerability with comparable activity.

[Formula: see text] The neuropsychological profile of children with Diffuse Intrinsic Pontine Glioma (DIPG) before and after radiation therapy: A prospective longitudinal study.

Children with Diffuse Intrinsic Pontine Gliomas (DIPG), a malignant brainstem tumor, experience poor prognosis. Because of the disease's rarity and highly aggressive course, there is a dearth of research on cognitive and psychosocial outcomes in this underserved, vulnerable population. However, evaluating effects of the disease and treatment on the cognitive and daily functioning of these patients is important to better understand their specific needs and improve their quality of life. The current longitudinal study administered prospective neuropsychological assessments to children diagnosed with CNS malignancies, including the largest sample of children with DIPG to date (n = 21, mean age = 7.86 years, range = 3-16) in neurocognitive, behavioral, social-emotional, and adaptive functioning at baseline, two weeks post-radiation, and six months later. The results describe population-based, cross-sectional characteristics and within-patient longitudinal changes. Prior to radiation, children with DIPG exhibited significant weaknesses compared to normative samples in both parent-report and performance-based measures of attention, and tests of processing speed and verbal learning/memory. Younger children demonstrated poorer inhibitory control on performance tests and worse parent-reported behavioral regulation, depression, and social withdrawal compared to older children. Six-months post-radiation, older children exhibited poorer socialization than younger children. Longitudinally, children with DIPG exhibited short-term improvements immediately post-radiation in performance-based attention tests and parent-reported behavior, including attention, hyperactivity, behavioral regulation, and executive function. However, these improvements did not persist and significant decline was documented on tests of attention by six months. Clinical implications for professionals working with children with DIPG and recommendations for cognitive remediation and quality of life interventions are provided.

Evaluation of the effect of a Nursing System Framework on Nurse Sensitive Indicators, mortality and readmission in an NHS Trust.

In 2018, an NHS Trust (UK) implemented an innovative Nursing System Framework (NSF). The NSF formalized a two-year strategy, which provided teams with clear aims and measurable objectives to deliver care. Failures of coordination of nursing services are well-recognized threats to the quality, safety and sustainability of care provision. AIM: To evaluate the efficacy of introducing a NSF in an NHS Trust, using nursing sensitive indicators and pre-selected mortality, data outcome measures. DESIGN: A before and after implementation, observational study. METHODS: 105,437 admissions were extracted at an admission record level. Data was extracted from 1st September 2018 through to the 31st August 2019. RESULTS: Using SQUIRE guidelines to report the study, insufficient evidence was found to reject a null hypothesis with a chi-squared test of association between in-hospital death and the NSF intervention period, with a p-value of .091. However, trends were seen in the data, which suggested a positive association. CONCLUSION: The NSF is a complex intervention, which provides direction for improvements but requires further research to understand the benefits for nurses, Midwives, Health Visitors and patients.

Response assessment in pediatric craniopharyngioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) Working Group.

BACKGROUND: Craniopharyngioma is a histologically benign tumor of the suprasellar region for which survival is excellent but quality of life is often poor secondary to functional deficits from tumor and treatment. Standard therapy consists of maximal safe resection with or without radiation therapy. Few prospective trials have been performed, and response assessment has not been standardized. METHODS: The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee devised consensus guidelines to assess craniopharyngioma response prospectively. RESULTS: Magnetic resonance imaging is the recommended radiologic modality for baseline and follow-up assessments. Radiologic response is defined by 2-dimensional measurements of both solid and cystic tumor components. In certain clinical contexts, response to solid and cystic disease may be differentially considered based on their unique natural histories and responses to treatment. Importantly, the committee incorporated functional endpoints related to neuro-endocrine and visual assessments into craniopharyngioma response definitions. In most circumstances, the cystic disease should be considered progressive only if growth is associated with acute, new-onset or progressive functional impairment. CONCLUSIONS: Craniopharyngioma is a common pediatric central nervous system tumor for which standardized response parameters have not been defined. A RAPNO committee devised guidelines for craniopharyngioma assessment to uniformly define response in future prospective trials.

Pediatric Central Nervous System Cancers, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Central nervous system (CNS) cancers account for approximately one quarter of all pediatric tumors and are the leading cause of cancer-related death in children. More than 4,000 brain and CNS tumors are diagnosed each year in children and teens, and the incidence rate has remained stagnant in recent years. The most common malignant pediatric CNS tumors are gliomas, embryonal tumors consisting of predominately medulloblastomas, and germ cell tumors. The inaugural version of the NCCN Guidelines for Pediatric Central Nervous System Cancers focuses on the diagnosis and management of patients with pediatric diffuse high-grade gliomas. The information contained in the NCCN Guidelines is designed to help clinicians navigate the complex management of pediatric patients with diffuse high-grade gliomas. The prognosis for these highly aggressive tumors is generally poor, with 5-year survival rates of <20% despite the use of combined modality therapies of surgery, radiation therapy and systemic therapy. Recent advances in molecular profiling has expanded the use of targeted therapies in patients whose tumors harbor certain alterations. However, enrollment in a clinical trial is the preferred treatment for eligible patients.

Single-dose pharmacokinetics and bioavailability of a novel extended duration transdermal buprenorphine solution in cats.

A novel transdermal buprenorphine solution (TBS) was developed for evaluation in order to make available an extended duration opioid analgesic for cats. Healthy adult cats were administered a single TBS dose of 10 mg (1.57-4.35 mg/kg), 30 mg (4.72-13.0 mg/kg), or 50 mg (7.87-21.7 mg/kg) (4 cats per group) applied topically to the unclipped dorsal cervical skin and plasma buprenorphine concentrations were evaluated through 7 days. To determine the absolute bioavailability of TBS, healthy cats were administered single TBS dose of 20 mg (3.33-4.76 mg/kg) or 0.05 mg (0.008-0.011 mg/kg) IV buprenorphine (6 cats per group). The mean ± standard deviation maximum plasma buprenorphine concentrations (Cmax ) were 10.5 ± 6.28, 18.6 ± 8.68, and 22.5 ± 4.47 ng/ml following 10, 30, and 50 mg doses, respectively, with the time of Cmax occurrence (tmax ) typically occurring at 2-12 h post-dosing. Mean plasma buprenorphine terminal half-lives ranged between 78.3 and 91.2 h. Increasing the dose threefold and fivefold from the 10 mg dose increased the exposure by 2.8- and 3.6-fold, respectively, indicating that plasma buprenorphine exposure increased in a less than proportional manner at doses >30 mg. Transient sedation, mydriasis, and euphoria were observed within 4 h post-dosing. Mean rectal temperatures were increased 0.6-0.9°C greater than baseline (37.4-37.8°C) through 168 h post-dosing. The absolute bioavailability was 16.0% (90% CI: [11.8%-21.7%]). Flip-flop pharmacokinetics were observed with a terminal elimination half-life of 0.82 ± 0.13 and 64.9 ± 15.0 h for IV buprenorphine and 20 mg of TBS, respectively. A single administration of TBS over a range of doses resulted in extended plasma buprenorphine concentrations and opioid physiological and behavioral effects.

Response assessment in paediatric intracranial ependymoma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.

Response criteria for paediatric intracranial ependymoma vary historically and across different international cooperative groups. The Response Assessment in the Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, neuro-radiologists, radiation oncologists, and neurosurgeons, was established to address both the issues and the unique challenges in assessing the response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric ependymoma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric ependymoma to clinical trial therapy. For areas in which data were scarce or unavailable, consensus was reached through an iterative process. RAPNO response assessment recommendations include assessing disease response on the basis of changes in tumour volume, and using event-free survival as a study endpoint for patients entering clinical trials without bulky disease. Our recommendations for response assessment include the use of brain and spine MRI, cerebral spinal fluid cytology, neurological examination, and steroid use. Baseline postoperative imaging to assess for residual tumour should be obtained 24-48 h after surgery. Our consensus recommendations and response definitions should be prospectively validated in clinical trials.

Vaccine Side Effects Following COVID-19 Vaccination Among the Residents of the UAE-An Observational Study.

COVID-19 vaccines have proven to be very safe in the clinical trials, however, there is less evidence comparing the safety of these vaccines in real-world settings. Therefore, we aim to investigate the nature and severity of the adverse effects reported and the differences based on the type of vaccine received. A survey was conducted among 1,878 adult (≥18 years) COVID-19 vaccine recipients through online survey platforms and telephonic interviews during March to September 2021. The factors potentially associated with the reported side effects like age, gender, ethnicity, comorbidities, and previous COVID-19 infection were analyzed based on the type of vaccine received. Differences in adverse events and the severity were compared between inactivated and mRNA vaccine recipients. The major adverse effects reported by the COVID-19 vaccine recipients were pain at the site of injection, fatigue and drowsiness, and headache followed by joint/muscle pain. The adverse effects were more common among recipients of mRNA Pfizer-BioNTech vaccine than among recipients of inactive Sinopharm vaccine with the odds ratio of 1.39 (95% CI 1.14-1.68). The average number of adverse effects reported between individuals who had received Sinopharm and Pfizer-BioNTech vaccines was 1.61 ± 2.08 and 2.20 ± 2.58, respectively, and the difference was statistically significant (p <0.001). Severe adverse effects after COVID-19 vaccinations were rare and 95% of the adverse effects reported after either an inactivated or mRNA vaccine were mild requiring no or home-based treatment. The study found that individuals less than 55 years of age, female gender, with history of one or more comorbid conditions, who had received mRNA Pfizer- BioNTech vaccine, and with history of COVID-19 infections are at higher odds of developing an adverse effect post COVID-19 vaccination compared to the others.

Joint EANM/SIOPE/RAPNO practice guidelines/SNMMI procedure standards for imaging of paediatric gliomas using PET with radiolabelled amino acids and [18F]FDG: version 1.0.

Positron emission tomography (PET) has been widely used in paediatric oncology. 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is the most commonly used radiopharmaceutical for PET imaging. For oncological brain imaging, different amino acid PET radiopharmaceuticals have been introduced in the last years. The purpose of this document is to provide imaging specialists and clinicians guidelines for indication, acquisition, and interpretation of [18F]FDG and radiolabelled amino acid PET in paediatric patients affected by brain gliomas. There is no high level of evidence for all recommendations suggested in this paper. These recommendations represent instead the consensus opinion of experienced leaders in the field. Further studies are needed to reach evidence-based recommendations for the applications of [18F]FDG and radiolabelled amino acid PET in paediatric neuro-oncology. These recommendations are not intended to be a substitute for national and international legal or regulatory provisions and should be considered in the context of good practice in nuclear medicine. The present guidelines/standards were developed collaboratively by the EANM and SNMMI with the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group and the Response Assessment in Paediatric Neuro-Oncology (RAPNO) working group. They summarize also the views of the Neuroimaging and Oncology and Theranostics Committees of the EANM and reflect recommendations for which the EANM and other societies cannot be held responsible.

Dual mTORC1/2 inhibition compromises cell defenses against exogenous stress potentiating Obatoclax-induced cytotoxicity in atypical teratoid/rhabdoid tumors.

Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors of infancy and have a dismal 4-year event-free survival (EFS) of 37%. We have previously shown that mTOR activation contributes to AT/RT's aggressive growth and poor survival. Targeting the mTOR pathway with the dual mTORC1/2 inhibitor TAK-228 slows tumor growth and extends survival in mice bearing orthotopic xenografts. However, responses are primarily cytostatic with limited durability. The aim of this study is to understand the impact of mTOR inhibitors on AT/RT signaling pathways and design a rational combination therapy to drive a more durable response to this promising therapy. We performed RNASeq, gene expression studies, and protein analyses to identify pathways disrupted by TAK-228. We find that TAK-228 decreases the expression of the transcription factor NRF2 and compromises AT/RT cellular defenses against oxidative stress and apoptosis. The BH3 mimetic, Obatoclax, is a potent inducer of oxidative stress and apoptosis in AT/RT. These complementary mechanisms of action drive extensive synergies between TAK-228 and Obatoclax slowing AT/RT cell growth and inducing apoptosis and cell death. Combination therapy activates the integrative stress response as determined by increased expression of phosphorylated EIF2α, ATF4, and CHOP, and disrupts the protective NOXA.MCL-1.BIM axis, forcing stressed cells to undergo apoptosis. Combination therapy is well tolerated in mice bearing orthotopic xenografts of AT/RT, slows tumor growth, and extends median overall survival. This novel combination therapy could be added to standard upfront therapies or used as a salvage therapy for relapsed disease to improve outcomes in AT/RT.

Immune response of booster doses of BBIBP-CORV vaccines against the variants of concern of SARS-CoV-2.

BACKGROUND: Booster doses for COVID-19 vaccinations are currently recommended and approved in many countries. However, we need more evidence on the immune response of individuals to booster doses of inactivated vaccines and the neutralizing effect against the variants of concerns of SARS-CoV-2. OBJECTIVE: To compare the fold reduction in antibody titers against the variants of concerns of SARS-CoV-2 between the primary doses and booster dose vaccine cohorts of inactivated BBIBP-CorV vaccine. STUDY DESIGN: In this observational study Plaque Reduction Neutralization Test (PRNT) assay was done on pooled serum samples of the recipients of primary two doses of inactivated BBIBP-CorV and on the pooled serum samples of recipients of a booster dose of inactive BBIBP-CorV. The neutralizing antibody titers against the wild (Wuhan) strain and the variants of concern (alpha, beta and delta) were compared. RESULTS: The serum sample pool from the booster cohort had high neutralizing antibody titers against the SARS-CoV-2 variants compared to the pooled serum samples of the recipients of primary two doses of inactivated BBIBP-CorV and the difference was statistically significant. The observed fold reduction in antibody titers from the serum pool of recipients of two doses of BBIBP-CorV vaccine were 3.7-fold, 14.6-fold and 10.4-fold compared to 1.8 -fold, 6.5-fold and 3.8-fold reduction against the alpha, beta and delta lineages respectively in the serum pool of recipient of a booster dose (three doses of BBIBP-CorV). CONCLUSION: Booster doses of inactive BBIBP-CORV offered better protection against the variants of concern of SARS-CoV-2.

GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas.

Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system1. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 106 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly3. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.

Clinical Trial Enrollment Among Adolescent and Young Adults with Primary Central Nervous System Tumors Treated at the Dana-Farber Cancer Institute.

Purpose: In recent decades, the survival outcomes among adolescent and young adults (AYAs, 15-39 years) have not improved substantially, especially among AYAs with primary central nervous system (CNS) tumors. While this is likely multifactorial, low participation in clinical trials among AYAs is thought to be a critical contributing factor. In this study, we describe the pattern of clinical trial enrollment among AYAs with primary CNS tumors at our institution. Methods: We performed a retrospective, IRB-approved chart review of AYAs with CNS tumors treated at the Dana-Farber Cancer Institute (DFCI) between January 2009 and December 2018. We used logistic regression analyses and descriptive statistics to analyze this sample and determine the clinical trial enrollment at the pediatric affiliate (Dana-Farber/Boston Children's Cancer and Blood Disorders Center) and adult affiliate (Dana-Farber/Brigham and Women's Cancer Center). Results: Ninety-three AYA patients with primary CNS tumors were treated at the Dana-Farber/Boston Children's Cancer and Blood Disorders Center, while 507 patients with primary CNS gliomas were treated at the Dana-Farber/Brigham and Women's Cancer Center. At the pediatric affiliate, 35.4% (33/93) of AYAs were enrolled in a therapeutic clinical trial, while at the adult affiliate, 15.8% (80/507) of AYAs were enrolled in a clinical trial. High-grade gliomas were associated with significantly higher rates of enrollment in the adult affiliate. Conclusions: Clinical trial enrollment remains poor among AYAs with CNS tumors, and clinical trial enrollment participation is modestly higher in the pediatric setting. Our study demonstrates the continued need to evaluate and address factors associated with clinical trial enrollment among AYAs with CNS tumors.

Liquid biopsy in gliomas: A RANO review and proposals for clinical applications.

BACKGROUND: There is an extensive literature highlighting the utility of blood-based liquid biopsies in several extracranial tumors for diagnosis and monitoring. METHODS: The RANO (Response Assessment in Neuro-Oncology) group developed a multidisciplinary international Task Force to review the English literature on liquid biopsy in gliomas focusing on the most frequently used techniques, that is circulating tumor DNA, circulating tumor cells, and extracellular vesicles in blood and CSF. RESULTS: ctDNA has a higher sensitivity and capacity to represent the spatial and temporal heterogeneity in comparison to circulating tumor cells. Exosomes have the advantages to cross an intact blood-brain barrier and carry also RNA, miRNA, and proteins. Several clinical applications of liquid biopsies are suggested: to establish a diagnosis when tissue is not available, monitor the residual disease after surgery, distinguish progression from pseudoprogression, and predict the outcome. CONCLUSIONS: There is a need for standardization of biofluid collection, choice of an analyte, and detection strategies along with rigorous testing in future clinical trials to validate findings and enable entry into clinical practice.

Deep learning-based automatic tumor burden assessment of pediatric high-grade gliomas, medulloblastomas, and other leptomeningeal seeding tumors.

BACKGROUND: Longitudinal measurement of tumor burden with magnetic resonance imaging (MRI) is an essential component of response assessment in pediatric brain tumors. We developed a fully automated pipeline for the segmentation of tumors in pediatric high-grade gliomas, medulloblastomas, and leptomeningeal seeding tumors. We further developed an algorithm for automatic 2D and volumetric size measurement of tumors. METHODS: The preoperative and postoperative cohorts were randomly split into training and testing sets in a 4:1 ratio. A 3D U-Net neural network was trained to automatically segment the tumor on T1 contrast-enhanced and T2/FLAIR images. The product of the maximum bidimensional diameters according to the RAPNO (Response Assessment in Pediatric Neuro-Oncology) criteria (AutoRAPNO) was determined. Performance was compared to that of 2 expert human raters who performed assessments independently. Volumetric measurements of predicted and expert segmentations were computationally derived and compared. RESULTS: A total of 794 preoperative MRIs from 794 patients and 1003 postoperative MRIs from 122 patients were included. There was excellent agreement of volumes between preoperative and postoperative predicted and manual segmentations, with intraclass correlation coefficients (ICCs) of 0.912 and 0.960 for the 2 preoperative and 0.947 and 0.896 for the 2 postoperative models. There was high agreement between AutoRAPNO scores on predicted segmentations and manually calculated scores based on manual segmentations (Rater 2 ICC = 0.909; Rater 3 ICC = 0.851). Lastly, the performance of AutoRAPNO was superior in repeatability to that of human raters for MRIs with multiple lesions. CONCLUSIONS: Our automated deep learning pipeline demonstrates potential utility for response assessment in pediatric brain tumors. The tool should be further validated in prospective studies.

Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR). METHODS: Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months). RESULTS: Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years (range 10-26.8). Median OS was 13 (2-82) months. The 1-, 3-, and 5-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and 1 was a LTS. The presence or absence of H3 alterations did not affect survival. CONCLUSION: Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.