Citations

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2–3 oligodendroglioma [1p19q codeleted, IDH- mutant], WHO grade 2–4 IDH- mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non–AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding molecular profiling of gliomas.

Abstract TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a co-inhibitory receptor, highly expressed by Tregs, and contributes to the suppressive function of Tregs by limiting pro-inflammatory Th1 and Th17 cell responses. Herein, we report that subsets of human regulatory B cells (Bregs) express surface TIGIT and can thus play a critical role in immune regulation. Using data from human B cell surface arrays and RNA-seq, we identified two major TIGIT+ human Bregs subsets, exhibiting CD24hiCD27+CD39hiIgD+IgMhiCD1chi marginal zone (MZ)-like and CD24hiCD27+CD39+IgD−IgM+CD1c+ memory Bregs. We further demonstrated that TIGIT+ Bregs were also capable of suppressing immune responses by their ability to express not only IL-10 and PD-L1, but also granzyme B and TGFb1. In addition, TIGIT+ Bregs can also suppress immune responses by altering dendritic cell functions. In line with these observations, liver allograft recipients with donor-specific alloantibody (DSA) had significantly lower numbers of TIGIT+ Bregs than those without DSA. Moreover, the frequency of TIGIT+ Bregs correlated with that of CD4+CD25+CD127lo Tregs, while it inversely correlated with the frequency of follicular helper T cells. We thus concluded that TIGIT+ Bregs play critical roles in immune regulation in liver allograft recipients.

AbstractBackgroundARIA is a common side effect of aducanumab, the first anti‐amyloid pharmacotherapy approved by the US Food and Drug Administration (FDA) to treat Alzheimer’s disease. Regular MRI is required by FDA to detect and monitor different forms of ARIA during initiation of therapy. MRI protocols must be a) high resolution to detect abnormalities with high sensitivity, b) fast to accommodate workflow and ensure patient compliance and c) standardized to maximize data acquisition consistency across sites. Based on a vendor agnostic protocol recommendation by Benzinger et al (CTAD 2021), we propose specific parameters for 3T Philips systems, for an accelerated and enhanced protocol.MethodThe protocol was developed on a 3T Philips Elition X scanner, using 32‐channel head coil, and included 3D T1, 3D FLAIR, 2D DWI, 2D T2* and multi echo 3D Susceptibility Weighted Imaging (SWI) sequences.ResultAcquisition voxel resolution of 3D T1, 3D FLAIR, T2* and DWI matches current recommendations. 3D SWI resolution is 0.7x0.7x2mm. Compressed‐SENSE (C‐SENSE) acceleration is applied on 3D T1, 3D FLAIR, T2* and 3D SWI. SENSE is applied on DWI (Figure 1). Total acquisition time including the additional 3D SWI scan is 11 minutes, 6 minutes faster than the original recommendation. Qualitative assessment of images showed high signal‐to‐noise and contrast‐to‐noise. Images were free of acceleration related artifacts. Automated slice prescription localizer ensures better reproducibility for longitudinal assessment.ConclusionImaging protocol standardization is necessary to ensure consistent accuracy for diagnosing ARIA. Broad recommendations leave room for variability, therefore specific parameters are needed to achieve cross‐platform standardization. Our protocol is applicable for 3T Philips systems with compressed‐SENSE capability and 32‐channel head coil. The recommended C‐SENSE values maintain image quality with shorter exam time. This is more comfortable for patients and easier to fit into the workflow. The higher sensitivity of SWI can improve thresholds for therapy monitoring and provide additional quantitative measurements.

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

Abstract Purpose: We sought to identify biomarkers that predict overall survival (OS) and response to immune checkpoint inhibitors (ICI) for patients with gastric cancer. Experimental Design: This was a retrospective study of multiple independent cohorts of patients with gastric cancer. The association between tumor ACTA2 expression and OS and ICI response were determined in patients whose tumors were analyzed with bulk mRNA sequencing. Single-cell RNA sequencing (scRNA-seq) and digital spatial profiling data were used to compare tumors from patients with gastric cancer who did and did not respond to ICI. Results: Increasing tumor ACTA2 expression was independently associated with worse OS in a 567-patient discovery cohort [HR, 1.28 per unit increase; 95% confidence interval (CI), 1.02–1.62]. This finding was validated in three independent cohorts (n = 974; HR, 1.52 per unit increase; 95% CI, 1.34–1.73). Of the 108 patients treated with ICI, 56% of patients with low ACTA2 expression responded to ICI versus 25% of patients with high ACTA2 expression (P = 0.004). In an analysis of a publicly available scRNA-seq dataset of 5 microsatellite instability-high patients treated with ICI, the patient who responded to ICI had lower tumor stromal ACTA2 expression than the 4 nonresponders. Digital spatial profiling of tumor samples from 4 ICI responders and 5 ICI nonresponders revealed that responders may have lower ACTA2 expression in α-SMA–positive cancer-associated fibroblasts (CAF) than nonresponders (median: 5.00 vs. 5.50). Conclusions: ACTA2 expression is associated with survival and ICI response in patients with gastric cancer. ACTA2 expression in CAFs, but not in other cellular compartments, appears to be associated with ICI response.

Background: We evaluated imaging features suggestive of neurodegeneration within the brainstem and upper cervical spinal cord (UCSC) in non-progressive multiple sclerosis (MS). Methods: Standardized 3-Tesla three-dimensional brain magnetic resonance imaging (MRI) studies were prospectively acquired. Rates of change in volume, surface texture, curvature were quantified at the pons and medulla-UCSC. Whole and regional brain volumes and T2-weighted lesion volumes were also quantified. Independent regression models were constructed to evaluate differences between those of Black or African ancestry (B/AA) and European ancestry (EA) with non-progressive MS. Results: 209 people with MS (pwMS) having at least two MRI studies, 29% possessing 3–6 timepoints, resulted in 487 scans for analysis. Median follow-up time between MRI timepoints was 1.33 (25th–75th percentile: 0.51–1.98) years. Of 183 non-progressive pwMS, 88 and 95 self-reported being B/AA and EA, respectively. Non-progressive pwMS demonstrated greater rates of decline in pontine volume ( p < 0.0001) in B/AA and in medulla-UCSC volume ( p < 0.0001) for EA pwMS. Longitudinal surface texture and curvature changes suggesting reduced tissue integrity were observed at the ventral medulla-UCSC ( p < 0.001), dorsal pons ( p < 0.0001) and dorsal medulla ( p < 0.0001) but not the ventral pons ( p = 0.92) between groups. Conclusions: Selectively vulnerable regions within the brainstem-UCSC may allow for more personalized approaches to disease surveillance and management.

AbstractBackgroundA recent phase III trial (NCT01372774) comparing use of stereotactic radiosurgery [SRS] versus whole-brain radiation therapy [WBRT] after surgical resection of a single brain metastasis revealed that declines in cognitive function were more common with WBRT than with SRS. A secondary endpoint in that trial, and the primary objective in this secondary analysis, was to identify baseline biomarkers associated with cognitive impairment after either form of radiotherapy for brain metastasis. Here we report our findings on APOE genotype and serum levels of associated proteins and their association with radiation-induced neurocognitive decline.MethodsIn this retrospective analysis of prospectively collected samples from a completed randomized clinical trial, patients provided blood samples every 3 months that were tested by genotyping and enzyme-linked immunosorbent assay, and results were analyzed in association with cognitive impairment.ResultsThe APOE genotype was not associated with neurocognitive impairment at 3 months. However, low serum levels of ApoJ, ApoE, or ApoA protein (all P &lt; .01) and higher amyloid beta (Aβ 1–42) levels (P = .048) at baseline indicated a greater likelihood of neurocognitive decline at 3 months after SRS, whereas lower ApoJ levels were associated with decline after WBRT (P = .014).ConclusionsPatients with these pretreatment serum markers should be counseled about radiation-related neurocognitive decline.

ImportanceAutoimmune encephalitis misdiagnosis can lead to harm.ObjectiveTo determine the diseases misdiagnosed as autoimmune encephalitis and potential reasons for misdiagnosis.Design, Setting, and ParticipantsThis retrospective multicenter study took place from January 1, 2014, to December 31, 2020, at autoimmune encephalitis subspecialty outpatient clinics including Mayo Clinic (n = 44), University of Oxford (n = 18), University of Texas Southwestern (n = 18), University of California, San Francisco (n = 17), Washington University in St Louis (n = 6), and University of Utah (n = 4). Inclusion criteria were adults (age ≥18 years) with a prior autoimmune encephalitis diagnosis at a participating center or other medical facility and a subsequent alternative diagnosis at a participating center. A total of 393 patients were referred with an autoimmune encephalitis diagnosis, and of those, 286 patients with true autoimmune encephalitis were excluded.Main Outcomes and MeasuresData were collected on clinical features, investigations, fulfillment of autoimmune encephalitis criteria, alternative diagnoses, potential contributors to misdiagnosis, and immunotherapy adverse reactions.ResultsA total of 107 patients were misdiagnosed with autoimmune encephalitis, and 77 (72%) did not fulfill diagnostic criteria for autoimmune encephalitis. The median (IQR) age was 48 (35.5-60.5) years and 65 (61%) were female. Correct diagnoses included functional neurologic disorder (27 [25%]), neurodegenerative disease (22 [20.5%]), primary psychiatric disease (19 [18%]), cognitive deficits from comorbidities (11 [10%]), cerebral neoplasm (10 [9.5%]), and other (18 [17%]). Onset was acute/subacute in 56 (52%) or insidious (&amp;gt;3 months) in 51 (48%). Magnetic resonance imaging of the brain was suggestive of encephalitis in 19 of 104 patients (18%) and cerebrospinal fluid (CSF) pleocytosis occurred in 16 of 84 patients (19%). Thyroid peroxidase antibodies were elevated in 24 of 62 patients (39%). Positive neural autoantibodies were more frequent in serum than CSF (48 of 105 [46%] vs 7 of 91 [8%]) and included 1 or more of GAD65 (n = 14), voltage-gated potassium channel complex (LGI1 and CASPR2 negative) (n = 10), N-methyl-d-aspartate receptor by cell-based assay only (n = 10; 6 negative in CSF), and other (n = 18). Adverse reactions from immunotherapies occurred in 17 of 84 patients (20%). Potential contributors to misdiagnosis included overinterpretation of positive serum antibodies (53 [50%]), misinterpretation of functional/psychiatric, or nonspecific cognitive dysfunction as encephalopathy (41 [38%]).Conclusions and RelevanceWhen evaluating for autoimmune encephalitis, a broad differential diagnosis should be considered and misdiagnosis occurs in many settings including at specialized centers. In this study, red flags suggesting alternative diagnoses included an insidious onset, positive nonspecific serum antibody, and failure to fulfill autoimmune encephalitis diagnostic criteria. Autoimmune encephalitis misdiagnosis leads to morbidity from unnecessary immunotherapies and delayed treatment of the correct diagnosis.

Objective The radiologically isolated syndrome (RIS) represents the earliest detectable pre‐clinical phase of multiple sclerosis (MS). This study evaluated the impact of therapeutic intervention in preventing first symptom manifestation at this stage in the disease spectrum. Methods We conducted a multi‐center, randomized, double‐blinded, placebo‐controlled study involving people with RIS. Individuals without clinical symptoms typical of MS but with incidental brain MRI anomalies consistent with central nervous system (CNS) demyelination were included. Within 12 MS centers in the United States, participants were randomly assigned 1:1 to oral dimethyl fumarate (DMF) 240 mg twice daily or placebo. The primary endpoint was the time to onset of clinical symptoms attributable to a CNS demyelinating event within a follow‐up period of 96 weeks. An intention‐to‐treat analysis was applied to all participating individuals in the primary and safety investigations. The study is registered at ClinicalTrials.gov , NCT02739542 (ARISE). Results Participants from 12 centers were recruited from March 9, 2016, to October 31, 2019, with 44 people randomized to dimethyl fumarate and 43 to placebo. Following DMF treatment, the risk of a first clinical demyelinating event during the 96‐week study period was highly reduced in the unadjusted Cox proportional‐hazards regression model (hazard ratio [HR] = 0.18, 95% confidence interval [CI] = 0.05–0.63, p = 0.007). More moderate adverse reactions were present in the DMF (34 [32%]) than placebo groups (19 [21%]) but severe events were similar (DMF, 3 [5%]; placebo, 4 [9%]). Interpretation This is the first randomized clinical trial demonstrating the benefit of a disease‐modifying therapy in preventing a first acute clinical event in people with RIS. ANN NEUROL 2023;93:604–614