A tough bioadhesive hydrogel supports sutureless sealing of the dural membrane in porcine and ex vivo human tissue.

Complete sequestration of central nervous system tissue and cerebrospinal fluid by the dural membrane is fundamental to maintaining homeostasis and proper organ function, making reconstruction of this layer an essential step during neurosurgery. Primary closure of the dura by suture repair is the current standard, despite facing technical, microenvironmental, and anatomic challenges. Here, we apply a mechanically tough hydrogel paired with a bioadhesive for intraoperative sealing of the dural membrane in rodent, porcine, and human central nervous system tissue. Tensile testing demonstrated that this dural tough adhesive (DTA) exhibited greater toughness with higher maximum stress and stretch compared with commercial sealants in aqueous environments. To evaluate the performance of DTA in the range of intracranial pressure typical of healthy and disease states, ex vivo burst pressure testing was conducted until failure after DTA or commercial sealant application on ex vivo porcine dura with a punch biopsy injury. In contrast to commercial sealants, DTA remained adhered to the porcine dura through increasing pressure up to 300 millimeters of mercury and achieved a greater maximum burst pressure. Feasibility of DTA to repair cerebrospinal fluid leak in a simulated surgical context was evaluated in postmortem human dural tissue. DTA supported effective sutureless repair of the porcine thecal sac in vivo. Biocompatibility and adhesion of DTA was maintained for up to 4 weeks in rodents after implantation. The findings suggest the potential of DTA to augment or perhaps even supplant suture repair and warrant further exploration.

A Drosophila model relevant to chemotherapy-related cognitive impairment.

Chemotherapy-related cognitive impairment (CRCI) is a common adverse effect of treatment and is characterized by deficits involving multiple cognitive domains including memory. Despite the significant morbidity of CRCI and the expected increase in cancer survivors over the coming decades, the pathophysiology of CRCI remains incompletely understood, highlighting the need for new model systems to study CRCI. Given the powerful array of genetic approaches and facile high throughput screening ability in Drosophila, our goal was to validate a Drosophila model relevant to CRCI. We administered the chemotherapeutic agents cisplatin, cyclophosphamide, and doxorubicin to adult Drosophila. Neurologic deficits were observed with all tested chemotherapies, with doxorubicin and in particular cisplatin also resulting in memory deficits. We then performed histologic and immunohistochemical analysis of cisplatin-treated Drosophila tissue, demonstrating neuropathologic evidence of increased neurodegeneration, DNA damage, and oxidative stress. Thus, our Drosophila model relevant to CRCI recapitulates clinical, radiologic, and histologic alterations reported in chemotherapy patients. Our new Drosophila model can be used for mechanistic dissection of pathways contributing to CRCI (and chemotherapy-induced neurotoxicity more generally) and pharmacologic screens to identify disease-modifying therapies.

A Drosophila model of chemotherapy-related cognitive impairment.

Chemotherapy-related cognitive impairment (CRCI) is a common adverse effect of treatment and is characterized by deficits involving multiple cognitive domains including memory. Despite the significant morbidity of CRCI and the expected increase in cancer survivors over the coming decades, the pathophysiology of CRCI remains incompletely understood, highlighting the need for new model systems to study CRCI. Given the powerful array of genetic approaches and facile high throughput screening ability in Drosophila, our goal was to validate a Drosophila model of CRCI. We administered the chemotherapeutic agents cisplatin, cyclophosphamide, and doxorubicin to adult Drosophila. Neurocognitive deficits were observed with all tested chemotherapies, especially cisplatin. We then performed histologic and immunohistochemical analysis of cisplatin-treated Drosophila tissue, demonstrating neuropathologic evidence of increased neurodegeneration, DNA damage, and oxidative stress. Thus, our Drosophila model of CRCI recapitulates clinical, radiologic, and histologic alterations reported in chemotherapy patients. Our new Drosophila model can be used for mechanistic dissection of pathways contributing to CRCI and pharmacologic screens to identify novel therapies to ameliorate CRCI.

The predictive value of partial MGMT promoter methylation for IDH-wild-type glioblastoma patients.

Background: Glioblastoma patients with hypermethylation of the O6-methylguanine-methyltransferase (MGMT) gene promoter have significantly improved survival when treated with temozolomide compared to patients with unmethylation of the MGMT promoter. However, the prognostic and predictive significance of partial MGMT promoter methylation is unclear. Methods: The National Cancer Database was queried for patients newly diagnosed in 2018 with histopathologically confirmed isocitrate dehydrogenase (IDH)-wildtype glioblastoma. The overall survival (OS) associated with MGMT promoter methylation status was assessed using multivariable Cox regression with Bonferroni correction for multiple testing (P < .008 was significant). Results: Three thousand eight hundred twenty-five newly diagnosed IDH-wildtype glioblastoma patients were identified. The MGMT promoter was unmethylated in 58.7% (n = 2245), partially methylated in 4.8% (n = 183), hypermethylated in 3.5% (n = 133), and methylated not otherwise specified (NOS; likely consisting predominantly of hypermethylated cases) in 33.0% (n = 1264) of cases. Among patients that received first-line single-agent chemotherapy (ie likely temozolomide), compared to partial methylation (referent), MGMT promoter unmethylation was associated with worse OS (hazard ratio [HR] 1.94; 95% confidence interval [95 CI]: 1.54-2.44; P < .001) in multivariable Cox regression adjusted for major prognostic confounders. In contrast, a significant OS difference was not observed between partially methylated promoters and either hypermethylated (HR 1.02; 95 CI: 0.72-1.46; P = .90) or methylated NOS (HR 0.99; 95 CI: 0.78-1.26; P = .93) promoters. Among IDH-wildtype glioblastoma patients who did not receive first-line chemotherapy, MGMT promoter methylation status was not associated with significant differences in OS (P = 0.39-0.83). Conclusions: Compared to MGMT promoter unmethylation, partial methylation was predictive of improved OS among IDH-wildtype glioblastoma patients treated with first-line single-agent chemotherapy-supporting the use of temozolomide therapy in these patients.

Focused Ultrasound Thalamotomy: Correlation of Postoperative Imaging with Neuropathological Findings.

Magnetic resonance-guided high-intensity focused ultrasound (MRgFUS) is a rapidly developing technique used for tremor relief in tremor-predominant Parkinson's disease (PD) and essential tremor that has demonstrated successful results. Here, we describe the neuropathological findings in a woman who died from a fall 10 days after successful MRgFUS for tremor-predominant PD. Histological analysis demonstrates the characteristic early postoperative MRI findings including 3 distinct zones on T2-weighted imaging: (1) a hypointense core, (2) a hyperintense region with hypointense rim, and (3) a slightly hyperintense, poorly marginated surrounding area. Histopathological analyses also demonstrate the suspected cellular processes composing each of these regions including central hemorrhagic necrosis with surrounding cytotoxic edema and a rim of mostly unaffected vasogenic edema with some reactive and reparative processes. Overall, this case demonstrates the correlation of postoperative imaging findings with the subacute neuropathological findings after MRgFUS for PD.

Benefits of Implementing an Enhanced Recovery After Surgery Protocol in Ambulatory Surgery.

Background: Enhanced recovery after surgery (ERAS) protocols in orthopaedic surgery have garnered significant focus due to their ability to control pain adequately in the immediate postoperative window, allowing for earlier mobilization, shorter hospital stays, and fewer complications. Virginia Commonwealth University created a multimodal pain management approach in which patients receive a preoperative femoral nerve block followed by periarticular intraoperative local injection anesthesia consisting of bupivacaine, ketamine, and ketorolac. Hypothesis: We hypothesized that implementation of the ERAS protocol will decrease postoperative pain scores, decrease recovery time in the postanesthesia care unit (PACU), and decrease opioid use in anterior cruciate ligament (ACL) reconstruction. Study Design: Cohort study; Level of evidence, 3. Methods: Two patient cohorts were involved: before ERAS implementation (pre-ERAS) and after (post-ERAS). Patients with ACL reconstruction only and patients with ACL reconstruction with meniscal repair were analyzed separately. Post-ERAS patients received an intraoperative periarticular injection of bupivacaine, ketamine, and ketorolac and a postoperative multimodal pain regimen. Outcomes included time spent in the PACU, short-term and long-term opioid consumption, and pain score at discharge from the PACU. Results: Compared with pre-ERAS patients, post-ERAS patients had decreased pain (2.1 vs 0.84 out of 10, respectively), spent less time in the PACU (79.4 vs 62.8 minutes, respectively), and had less opioid consumption in the immediate postoperative period (4.55 vs 2.26 total morphine milligram equivalents [MMEs], respectively) (P < .001 for all). After ERAS implementation, long-term MME use decreased from 410 to 321 between 0 and 2 weeks postoperatively, 92.6 to 1.69 between 2 and 6 weeks, and 494.5 to 323 between 0 and 6 weeks (P < .001 for all). All domains showed significant improvements for both the ACL and the ACL plus meniscal repair cohorts, with the exception of pain at discharge in the ACL plus meniscal repair group. Conclusion: The study findings suggest that an enhanced recovery pathways protocol that includes a standardized intraoperative periarticular bupivacaine, ketamine, and ketorolac injection improves pain scores in the immediate postoperative window, decreases opioid consumption, and reduces recovery time in the PACU for patients undergoing ACL reconstruction.

The epidemiology of primary and metastatic brain tumors in infancy through childhood.

PURPOSE: To evaluate the epidemiology of primary and metastatic pediatric brain tumors in the United States according to the WHO CNS 4th and 5th editions classifications. METHODS: Pediatric patients (age ≤ 14) presenting between 2004 and 2017 with a brain tumor were identified in the National Cancer Database and categorized by NICHD age stages. Patients' age, sex, race/ethnicity, overall survival, and tumor characteristics were evaluated according to WHO CNS 4th and 5th editions. RESULTS: 23,978 pediatric brain tumor patients were identified. Overall, other (i.e. circumscribed) astrocytic gliomas (21%), diffuse astrocytic/oligodendroglial gliomas (21%; 64% of which were midline), and embryonal tumors (16%) predominated. A minority of brain tumors were of ependymal (6%), glioneuronal & neuronal (6%), germ cell tumor (GCT; 4%), mesenchymal non-meningothelial (2%), cranial nerve (2%), choroid plexus (2%), meningioma (2%), pineal (1%), and hematolymphoid (0.4%) types. GCTs were more likely in patients of Asian/Pacific Islander race/ethnicity. Brain metastases were exceedingly rare, accounting for 1.4% overall, with the most common primary tumor being neuroblastoma (61%) and non-CNS sarcoma (16%). Brain metastatic, choroid plexus, and embryonal tumors peaked during infancy and toddlerhood; whereas diffuse gliomas peaked in middle-late childhood. GCTs and glioneuronal & neuronal tumors uniquely displayed bimodal distributions, with elevated prevalence in both infancy and middle-to-late childhood. CONCLUSION: We systematically described the epidemiology of pediatric brain tumors in the context of contemporary classification schema, thereby validating our current understanding and providing key insights.

The phenomenon of clasmatodendrosis.

Clasmatodendrosis derives from the Greek for fragment (klasma), tree (dendron), and condition (- osis). Cajal first used the term in 1913: he observed disintegration of the distal cell processes of astrocytes, along with a fragmentation or beading of proximal processes closer to the astrocyte cell body. In contemporary clinical and experimental reports, clasmatodendrosis has been observed in models of cerebral ischemia and seizures (including status epilepticus), in elderly brains, in white matter disease, in hippocampal models and cell cultures associated with amyloid plaques, in head trauma, toxic exposures, demyelinating diseases, encephalitides and infection-associated encephalopathies, and in the treatment of cancer using immune effector cells. We examine evidence to support a claim that clasmatodendrotic astrocyte cell processes overtly bead (truncate) as a morphological sign of ongoing damage premortem. In grey and white matter and often in relationship to vascular lumina, beading becomes apparent with immunohistochemical staining of glial fibrillary acidic protein when specimens are examined at reasonably high magnification, but demonstration of distal astrocytic loss of processes may require additional marker study and imaging. Proposed mechanisms for clasmatodendrotic change have examined hypoxic-ischemic, osmotic-demyelinating, and autophagic models. In these models as well as in neuropathological reports, parenchymal swelling, vessel-wall leakage, or disturbed clearance of toxins can occur in association with clasmatodendrosis. Clasmatodendrotic features may serve as a marker for gliovascular dysregulation either acutely or chronically. We review correlative evidence for blood-brain barrier (BBB) dysfunction associated with astrocytic structural change, with attention to interactions between endothelial cells, pericytes, and astrocytic endfeet.

Elevated Oxidative Stress and DNA Damage in Cortical Neurons of Chemotherapy Patients.

The unintended neurologic sequelae of chemotherapy contribute to significant patient morbidity. Chemotherapy-related cognitive impairment (CRCI) is observed in up to 80% of cancer patients treated with chemotherapy and involves multiple cognitive domains including executive functioning. The pathophysiology underlying CRCI and the neurotoxicity of chemotherapy is incompletely understood, but oxidative stress and DNA damage are highly plausible mechanisms based on preclinical data. Unfortunately, validating pathways relevant to CRCI in humans is limited by an absence of relevant neuropathologic studies of patient brain tissue. In the present study, we stained sections of frontal lobe autopsy tissue from cancer patients treated with chemotherapy (n = 15), cancer patients not treated with chemotherapy (n = 10), and patients without history of cancer (n = 10) for markers of oxidative stress (nitrotyrosine, 4-hydroxynonenal) and DNA damage (pH2AX, pATM). Cancer patients treated with chemotherapy had increased staining for markers of oxidative stress and DNA damage in frontal lobe cortical neurons compared to controls. We detected no statistically significant difference in oxidative stress and DNA damage by the duration between last administration of chemotherapy and death. The study highlights the potential relevance of oxidative stress and DNA damage in the pathophysiology of CRCI and the neurotoxicity of chemotherapy.

IDH-mutant gliomas with additional class-defining molecular events.

The 2016 WHO classifies IDH-mutant gliomas into oligodendroglioma or diffuse astrocytoma based on co-occurring genetic events. Recent literature addresses the concept of stratifying IDH-mutant gliomas based on prognostically significant molecular events. However, the presence of a second class-defining driver alteration in IDH-mutant gliomas has not been systematically described. We searched the sequencing database at our institutions as well as The Cancer Genome Atlas (TCGA) and cBioPortal for IDH-mutant gliomas with other potentially significant alterations. For each case, we reviewed the clinical information, histology and genetic profile. Of 1702 gliomas tested on our targeted exome sequencing panel, we identified 364 IDH-mutated gliomas, four of which had pathogenic FGFR alterations and one with BRAF V600E mutation. Five additional IDH-mutant gliomas with NTRK fusions were identified through collaboration with an outside institution. Also, a search in the glioma database in cBioPortal (5379 total glioma samples, 1515 cases [28.1%] with IDH1/2 mutation) revealed eight IDH-mutated gliomas with FGFR, NTRK or BRAF pathogenic alterations. All IDH-mutant gliomas with dual mutations identified were hemispheric and had a mean age at diagnosis of 36.2 years (range 16-55 years old). Co-occurring genetic events involved MYCN, RB and PTEN. Notable outcomes included a patient with an IDH1/FGFR1-mutated anaplastic oligodendroglioma who has survived 20 years after diagnosis. We describe a series of 18 IDH-mutant gliomas with co-occurring genetic events that have been described as independent class-defining drivers in other gliomas. While these tumors are rare and the significance of these alterations needs further exploration, alterations in FGFR, NTRK, and BRAF could have potential therapeutic implications and affect clinical trial design and results in IDH-mutant studies. Our data highlights that single gene testing for IDH1 in diffuse gliomas may be insufficient for detection of targets with potential important prognostic and treatment value.

Expanded Clinical Phenotype, Oncological Associations, and Immunopathologic Insights of Paraneoplastic Kelch-like Protein-11 Encephalitis.

Importance: Recognizing the presenting and immunopathological features of Kelch-like protein-11 immunoglobulin G seropositive (KLHL11 IgG+) patients may aid in early diagnosis and management. Objective: To describe expanding neurologic phenotype, cancer associations, outcomes, and immunopathologic features of KLHL11 encephalitis. Design, Setting, and Participants: This retrospective tertiary care center study, conducted from October 15, 1998, to November 1, 2019, prospectively identified 31 KLHL11 IgG+ cases in the neuroimmunology laboratory. Eight were identified by retrospective testing of patients with rhomboencephalitis (confirmed by tissue-based-immunofluorescence and transfected-cell-based assays). Main Outcomes and Measures: Outcome variables included modified Rankin score and gait aid use. Results: All 39 KLHL11 IgG+ patients were men (median age, 46 years; range, 28-73 years). Initial clinical presentations were ataxia (n = 32; 82%), diplopia (n = 22; 56%), vertigo (n = 21; 54%), hearing loss (n = 15; 39%), tinnitus (n = 14; 36%), dysarthria (n = 11; 28%), and seizures (n = 9; 23%). Atypical neurologic presentations included neuropsychiatric dysfunction, myeloneuropathy, and cervical amyotrophy. Hearing loss or tinnitus preceded other neurologic deficits by 1 to 8 months in 10 patients (26%). Among patients screened for malignancy (n = 36), testicular germ-cell tumors (n = 23; 64%) or testicular microlithiasis and fibrosis concerning for regressed germ cell tumor (n = 7; 19%) were found in 83% of the patients (n = 30). In 2 patients, lymph node biopsy diagnosed metastatic lung adenocarcinoma in one and chronic lymphocytic leukemia in the other. Initial brain magnetic resonance imaging revealed T2 hyperintensities in the temporal lobe (n = 12), cerebellum (n = 9), brainstem (n = 3), or diencephalon (n = 3). Among KLHL11 IgG+ patients who underwent HLA class I and class II genotyping (n = 10), most were found to have HLA-DQB1*02:01 (n = 7; 70%) and HLA-DRB1*03:01 (n = 6; 60%) associations. A biopsied gadolinium-enhancing temporal lobe lesion demonstrated T cell-predominant inflammation and nonnecrotizing granulomas. Cerebellar biopsy (patient with chronic ataxia) and 2 autopsied brains demonstrated Purkinje neuronal loss and Bergmann gliosis, supporting early active inflammation and later extensive neuronal loss. Compared with nonautoimmune control peripheral blood mononuclear cells, cluster of differentiation (CD) 8+ and CD4+ T cells were significantly activated when patient peripheral blood mononuclear cells were cultured with KLHL11 protein. Most patients (58%) benefitted from immunotherapy and/or cancer treatment (neurological disability stabilized [n = 10] or improved [n = 9]). Kaplan-Meier curve demonstrated significantly higher probability of wheelchair dependence among patients without detectable testicular cancer. Long-term outcomes in KLHL11-IgG+ patients were similar to Ma2 encephalitis. Conclusions and Relevance: Kelch-like protein-11 IgG is a biomarker of testicular germ-cell tumor and paraneoplastic neurologic syndrome, often refractory to treatment. Described expanded neurologic phenotype and paraclinical findings may aid in its early diagnosis and treatment.

Molecular and clinicopathologic features of gliomas harboring NTRK fusions.

Fusions involving neurotrophic tyrosine receptor kinase (NTRK) genes are detected in ≤2% of gliomas and can promote gliomagenesis. The remarkable therapeutic efficacy of TRK inhibitors, which are among the first Food and Drug Administration-approved targeted therapies for NTRK-fused gliomas, has generated significant clinical interest in characterizing these tumors. In this multi-institutional retrospective study of 42 gliomas with NTRK fusions, next generation DNA sequencing (n = 41), next generation RNA sequencing (n = 1), RNA-sequencing fusion panel (n = 16), methylation profile analysis (n = 18), and histologic evaluation (n = 42) were performed. All infantile NTRK-fused gliomas (n = 7) had high-grade histology and, with one exception, no other significant genetic alterations. Pediatric NTRK-fused gliomas (n = 13) typically involved NTRK2, ranged from low- to high-histologic grade, and demonstrated histologic overlap with desmoplastic infantile ganglioglioma, pilocytic astrocytoma, ganglioglioma, and glioblastoma, among other entities, but they rarely matched with high confidence to known methylation class families or with each other; alterations involving ATRX, PTEN, and CDKN2A/2B were present in a subset of cases. Adult NTRK-fused gliomas (n = 22) typically involved NTRK1 and had predominantly high-grade histology; genetic alterations involving IDH1, ATRX, TP53, PTEN, TERT promoter, RB1, CDKN2A/2B, NF1, and polysomy 7 were common. Unsupervised principal component analysis of methylation profiles demonstrated no obvious grouping by histologic grade, NTRK gene involved, or age group. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, MAPK, and other pathways. In summary, the study highlights the clinical, histologic, and molecular heterogeneity of NTRK-fused gliomas, particularly when stratified by age group.

Molecular characterization of diffuse malignant peritoneal mesothelioma.

Malignant peritoneal mesothelioma is a rare aggressive tumor that arises from the peritoneal lining. While recurrent BAP1 mutations have been identified in a subset of mesotheliomas, molecular characteristics of peritoneal mesotheliomas, including those lacking BAP1 alterations, remain poorly understood. Using targeted next-generation sequencing, we examined the molecular features of 26 diffuse malignant peritoneal mesotheliomas. As part of an exploratory analysis, we analyzed an additional localized peritoneal mesothelioma and one well-differentiated papillary mesothelioma with invasive foci. Genomic characterization identified categories of diffuse malignant peritoneal mesotheliomas: The first group included 18 (69%) tumors with recurrent BAP1 alterations, with eight (31%) having more than one BAP1 alterations, and concomitant alterations in PBRM1 (46%) and SETD2 (35%). All tumors with complete loss of BAP1 expression by immunohistochemistry harbored BAP1 molecular alterations. PBRM1 alterations were significantly enriched in the BAP1-altered cohort. Frequent copy number loss of BAP1, ARID1B, PRDM1, PBRM1, SETD2, NF2, and CDKN2A was noted. The second group included eight (31%) BAP1-wild-type tumors: two with TP53 mutations, one with a TRAF7 activating mutation, one with a SUZ12 inactivating mutation, and three with ALK rearrangements that we previously published. One TP53-mutant biphasic mesothelioma showed evidence of genomic near-haploidization showing loss of heterozygosity of all chromosomes except 5, 7, 16, and 20. The localized peritoneal mesothelioma harbored a nonsense CHEK2 mutation, and the well-differentiated papillary mesothelioma with invasive foci harbored no reportable variants. In conclusion, we described the genetic categories of diffuse malignant peritoneal mesotheliomas, with BAP1-mutant and BAP1-wild-type groups. Our findings implicated DNA repair, epigenetics, and cell cycle regulation in the pathogenesis of peritoneal mesotheliomas, with identification of potential therapeutic targets.

Iatrogenic Neuropathology of Systemic Therapies.

Administration of systemic antineoplastic agents can result in adverse neurologic events. We describe the clinicopathologic features and putative mechanisms underlying iatrogenic neuropathology of the central nervous system secondary to chimeric antigen receptor (CAR) T-cell therapy and conventional chemotherapy.

Integration of rare cell capture technology into cytologic evaluation of cerebrospinal fluid specimens from patients with solid tumors and suspected leptomeningeal metastasis.

INTRODUCTION: Dissemination of tumor to the leptomeninges, subarachnoid space, and cerebrospinal fluid (CSF) is termed leptomeningeal metastasis (LM) and occurs in approximately 5% of patients with solid tumors. LM is associated with dismal clinical prognosis, and routine cytologic and radiologic methods for diagnosing LM have limited sensitivity. The CellSearch immunomagnetic rare cell capture assay is FDA-approved to detect circulating tumor cells (CTCs) in peripheral blood, but whether it may have a role in identifying CSF CTCs is still unclear. MATERIAL AND METHODS: CSF specimens from 20 patients with clinically suspected solid tumor LM collected from 2 institutions between October 2016 and January 2019 were evaluated with routine CSF cytology and underwent concurrent CTC testing with the CellSearch assay (Menarini-Silicon Biosystems, Huntingdon Valley, PA). The results of CTC testing were compared to routine CSF cytology and radiologic studies for detecting LM. RESULTS: The CellSearch assay achieved a sensitivity of 88.9% and specificity of 100% for detecting LM (using a threshold of 1 CTC/mL of CSF as the definition of a positive CTC result). One patient with negative CSF cytology but positive CTCs developed positive cytology 37 days later. CONCLUSIONS: In this proof-of-principle pilot study, we demonstrate that the CellSearch assay can be successfully integrated with the routine CSF cytologic workflow to aid in the diagnosis of solid tumor LM. Importantly, CTCs detected by this rare cell capture assay are found in a subset of patients with non-positive routine CSF cytology, which may have significant implications for patient management.

Predictors and early survival outcomes of maximal resection in WHO grade II 1p/19q-codeleted oligodendrogliomas.

BACKGROUND: Although surgery plays a crucial diagnostic role in World Health Organization (WHO) grade II 1p/19q-codeleted oligodendrogliomas, the role of maximal tumor surgical resection remains unclear, with early retrospective series limited by lack of molecular classification or appropriate control groups. METHODS: The characteristics, management, and overall survival (OS) of patients ≥20 years old presenting with histology-proven WHO grade II 1p/19q-codeleted oligodendrogliomas during 2010-2016 were evaluated using the National Cancer Database and validated using multi-institutional data. Patients were stratified by watchful waiting (biopsy only) versus surgical resection. OS was analyzed using Kaplan-Meier methods and risk-adjusted proportional hazards. RESULTS: Five hundred ninety adults met inclusion criteria, of whom 79.0% (n = 466) underwent surgical resection. Of patient and tumor characteristics, younger patients were more likely to be resected. Achieving gross total resection (GTR; n = 320) was significantly associated with smaller tumors, management at integrated network cancer programs (vs community cancer programs), and Medicare insurance (as compared with no, private, or Medicaid/other government insurance) and independent of other patient or tumor characteristics. In risk-adjusted analyses, GTR, but not subtotal resection (STR), demonstrated improved OS (vs biopsy only: hazard ratio 0.28, 95% CI: 0.09-0.85, P = 0.02). CONCLUSIONS: WHO grade II 1p/19q-codeleted oligodendrogliomas amenable to resection demonstrated improved OS with GTR, but not STR, compared with biopsy-only watchful waiting. The OS benefits of GTR were independent of age, tumor size, or tumor location. Medicare-insured and integrated network cancer program patients were significantly more likely to have GTR than other patients, suggesting that insurance status and care setting may play important roles in access to timely diagnosis or innovations that improve maximal resection.

Characterization of molecular signatures of supratentorial ependymomas.

Ependymomas show poor correlation between World Health Organization grade and clinical outcome. A subgroup of supratentorial ependymomas are characterized by C11orf95-RELA fusions, presumed to be secondary to chromothripsis of chromosome 11, resulting in constitutive activation of the NF-κB signaling pathway and overexpression of cyclin D1, p65, and L1 cell adhesion molecule (L1CAM). These RELA-fused ependymomas are recognized as a separate, molecularly defined World Health Organization entity and might be associated with poor clinical outcome. In this study, we show that immunohistochemistry for NF-κB signaling components, such as L1CAM, p65, and cyclin D1, can help distinguish RELA-fused from non-RELA-fused supratentorial ependymomas. Furthermore, these three markers can reliably differentiate RELA-fused ependymomas from a variety of histologic mimics. Lastly, we report that RELA-fused ependymomas may be associated with different chromosomal copy number changes and molecular alterations compared to their non-RELA-fused counterparts, providing additional insight into the genetic pathogenesis of these tumors and potential targets for directed therapies.

Neurological toxicities associated with chimeric antigen receptor T-cell therapy.

Chimeric antigen receptor T cell therapy has become an important tool in the treatment of relapsed and refractory malignancy; however, it is associated with significant neurological toxicity. We characterized the neurological toxicity associated with chimeric antigen receptor T-cell therapy in a consecutive series of 100 patients up to 2 months post transfusion, 28 of whom were obtained from chart review and the others by prospective observation. The underlying neoplasms were lymphoma (74%), myeloma (14%), leukaemia (10%), and sarcoma (2%). The median age of the cohort was 64.5 years old and 39% of patients were female. The most commonly occurring neurological symptoms were encephalopathy (57%), headache (42%), tremor (38%), aphasia (35%) and focal weakness (11%). Focal neurological deficits are frequently observed after chimeric antigen receptor T-cell therapy and are associated with regional EEG abnormalities, FDG-PET hypometabolism, and elevated velocities on transcranial Doppler ultrasound. In contrast, structural imaging was typically normal. As this form of treatment is more widely adopted, recognition of the frequently encountered symptoms will be of increasing importance for the neurologists and oncologists caring for this growing patient population.