Generative Adversarial Networks to Synthesize Missing T1 and FLAIR MRI Sequences for Use in a Multisequence Brain Tumor Segmentation Model.

Background Missing MRI sequences represent an obstacle in the development and use of deep learning (DL) models that require multiple inputs. Purpose To determine if synthesizing brain MRI scans using generative adversarial networks (GANs) allows for the use of a DL model for brain lesion segmentation that requires T1-weighted images, postcontrast T1-weighted images, fluid-attenuated inversion recovery (FLAIR) images, and T2-weighted images. Materials and Methods In this retrospective study, brain MRI scans obtained between 2011 and 2019 were collected, and scenarios were simulated in which the T1-weighted images and FLAIR images were missing. Two GANs were trained, validated, and tested using 210 glioblastomas (GBMs) (Multimodal Brain Tumor Image Segmentation Benchmark [BRATS] 2017) to generate T1-weighted images from postcontrast T1-weighted images and FLAIR images from T2-weighted images. The quality of the generated images was evaluated with mean squared error (MSE) and the structural similarity index (SSI). The segmentations obtained with the generated scans were compared with those obtained with the original MRI scans using the dice similarity coefficient (DSC). The GANs were validated on sets of GBMs and central nervous system lymphomas from the authors' institution to assess their generalizability. Statistical analysis was performed using the Mann-Whitney, Friedman, and Dunn tests. Results Two hundred ten GBMs from the BRATS data set and 46 GBMs (mean patient age, 58 years ± 11 [standard deviation]; 27 men [59%] and 19 women [41%]) and 21 central nervous system lymphomas (mean patient age, 67 years ± 13; 12 men [57%] and nine women [43%]) from the authors' institution were evaluated. The median MSE for the generated T1-weighted images ranged from 0.005 to 0.013, and the median MSE for the generated FLAIR images ranged from 0.004 to 0.103. The median SSI ranged from 0.82 to 0.92 for the generated T1-weighted images and from 0.76 to 0.92 for the generated FLAIR images. The median DSCs for the segmentation of the whole lesion, the FLAIR hyperintensities, and the contrast-enhanced areas using the generated scans were 0.82, 0.71, and 0.92, respectively, when replacing both T1-weighted and FLAIR images; 0.84, 0.74, and 0.97 when replacing only the FLAIR images; and 0.97, 0.95, and 0.92 when replacing only the T1-weighted images. Conclusion Brain MRI scans generated using generative adversarial networks can be used as deep learning model inputs in case MRI sequences are missing. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Zhong in this issue. An earlier incorrect version of this article appeared online. This article was corrected on April 12, 2021.

Glioma risk associated with extent of estimated European genetic ancestry in African Americans and Hispanics.

Glioma incidence is highest in non-Hispanic Whites, and to date, glioma genome-wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case-Control Study and GliomaSE Case-Control Study previously estimated to have <80% EA, or self-identify as non-White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with ≥40% AA (AFR≥0.4 ), and ≥15% NAA (AMR≥0.15 ), genome-wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 × 10-4 ; 11p11.12, p = 7.0 × 10-4 ) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR≥0.4 . In addition, we identified a peak at rs1620291 (p = 4.36 × 10-6 ) in 7q21.3. Among AMR≥0.15 , we found an association between increased EA in one region (12q24.21, p = 8.38 × 10-4 ), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 × 10-4 ). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies.

Scrambler therapy for chemotherapy neuropathy: a randomized phase II pilot trial.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is a prominent clinical problem, with limited effective therapies. Preliminary non-randomized clinical trial data support that Scrambler Therapy is helpful in this situation. METHODS: Patients were eligible if they had CIPN symptoms for at least 3 months and CIPN-related tingling or pain at least 4/10 in severity during the week prior to registration. They were randomized to receive Scrambler Therapy versus transcutaneous electrical nerve stimulation (TENS) for 2 weeks. Patient-reported outcomes (PROs) were utilized to measure efficacy and toxicity daily for 2 weeks during therapy and then weekly for 8 additional weeks. RESULTS: This study accrued 50 patients, 25 to each of the 2 study arms; 46 patients were evaluable. There were twice as many Scrambler-treated patients who had at least a 50% documented improvement during the 2 treatment weeks, from their baseline pain, tingling, and numbness scores, when compared with the TENS-treated patients (from 36 to 56% compared with 16-28% for each symptom). Global Impression of Change scores for "neuropathy symptoms," pain, and quality of life were similarly improved during the treatment weeks. Patients in the Scrambler group were more likely than those in the TENS group to recommend their treatment to other patients, during both the 2-week treatment period and the 8-week follow-up period (p < 0.0001). Minimal toxicity was observed. CONCLUSIONS: The results from this pilot trial were positive, supporting the conduct of further investigations regarding the use of Scrambler Therapy for treating CIPN.

Age-specific genome-wide association study in glioblastoma identifies increased proportion of 'lower grade glioma'-like features associated with younger age.

Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age-at-diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age-at-diagnosis has been explored, genome-wide association studies (GWAS) have not previously been stratified by age. Potential age-specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18-53, 54-64, 65+) datasets were analyzed using age-stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta-analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p54-63 = 1.50x10-9 , OR54-63 = 1.28, 95%CI54-63 = 1.18-1.39; p64+ = 2.14x10-11 , OR64+ = 1.32, 95%CI64+ = 1.21-1.43] and rs11979158 [p54-63 = 6.13x10-8 , OR54-63 = 1.35, 95%CI54-63 = 1.21-1.50; p64+ = 2.18x10-10 , OR64+ = 1.42, 95%CI64+ = 1.27-1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18-53 (p18-53 = 9.30 × 10-11 , OR18-53 = 1.76, 95%CI18-53 = 1.49-2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of 'LGG'-like tumor characteristics in GBM samples in those 18-53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54-63] and 0.8% [64+] (p = 0.0005). Age-specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18-53 suggests that more younger individuals may present initially with 'secondary glioblastoma.'

Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors.

BACKGROUND: The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants. METHODS: We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants. RESULTS: Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants. CONCLUSIONS: Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. (Funded by the National Institutes of Health and others.).

Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG-positive patients.

OBJECTIVE: To describe an expanded phenotypic spectrum and longitudinal outcome in 256 LGI1-IgG-seropositive and/or CASPR2-IgG-seropositive patients. METHODS: Patients were identified through service neural autoantibody evaluation. Ninety-five had longitudinal follow-up (7-456 months; median = 35). RESULTS: Among 3,910 patients tested, 196 were LGI1-IgG positive, 51 were CASPR2-IgG positive, and 9 were dual positive. Cerebrospinal fluid testing was less sensitive than serum testing, detecting only 24 of 38 (63%) LGI1-IgG-positive and 5 of 6 (83%) CASPR2-IgG-positive patients. LGI1-IgG-positive specimens had higher voltage-gated potassium channel-IgG immunoprecipitation values (0.33nmol/l, range = 0.02-5.14) than CASPR2-IgG-positive specimens (0.10nmol/l, range = 0.00-0.45, p < 0.001). Of patients presenting with pain or peripheral nervous system (PNS) manifestations, 39% were LGI1-IgG seropositive (7% had solely neuropathy or pain). Multivariate analysis identified age as the only significant predictor of central nervous system (CNS) versus PNS involvement (>50 years; odds ratio = 15, p < 0.001). Paroxysmal dizziness spells (PDS), a unique LGI1-IgG accompaniment (14% of patients), frequently delayed the diagnosis. T2-mesiotemporal hyperintensity was more common in LGI1-IgG-positive (41%) than in CASPR2-IgG-positive patients (p = 0.033). T1-bright basal ganglia were confined to LGI1-IgG-positive patients with faciobrachial-dystonic seizures (9 of 39, 31%). Cancer was found in 44% of LGI1-IgG/CASPR2-IgG dual seropositive patients (one-third thymoma). Response to initial immunotherapy was favorable in 97%; mean modified Rankin score was 3 (range = 1-5) at onset and 1.74 (range = 0-6) at last follow-up, with 9% having severe refractory disability, 20% being asymptomatic, 28% receiving immunotherapy, and 58% receiving antiepileptic medication. INTERPRETATION: Older age is a strong predictor of CNS involvement in patients seropositive for CASPR2-IgG or LGI1-IgG. Pain, peripheral manifestations, and stereotypic paroxysmal dizziness spells are common with LGI1-IgG. Response to initial immunotherapy is often favorable, but some patients remain severely disabled, requiring long-term immunotherapy and/or antiepileptic medications. Ann Neurol 2017;82:79-92.

Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT.

The "integrated diagnosis" for infiltrating gliomas in the 2016 revised World Health Organization (WHO) classification of tumors of the central nervous system requires assessment of the tumor for IDH mutations and 1p/19q codeletion. Since TERT promoter mutations and ATRX alterations have been shown to be associated with prognosis, we analyzed whether these tumor markers provide additional prognostic information within each of the five WHO 2016 categories. We used data for 1206 patients from the UCSF Adult Glioma Study, the Mayo Clinic and The Cancer Genome Atlas (TCGA) with infiltrative glioma, grades II-IV for whom tumor status for IDH, 1p/19q codeletion, ATRX, and TERT had been determined. All cases were assigned to one of 5 groups following the WHO 2016 diagnostic criteria based on their morphologic features, and IDH and 1p/19q codeletion status. These groups are: (1) Oligodendroglioma, IDH-mutant and 1p/19q-codeleted; (2) Astrocytoma, IDH-mutant; (3) Glioblastoma, IDH-mutant; (4) Glioblastoma, IDH-wildtype; and (5) Astrocytoma, IDH-wildtype. Within each group, we used univariate and multivariate Cox proportional hazards models to assess associations of overall survival with patient age at diagnosis, grade, and ATRX alteration status and/or TERT promoter mutation status. Among Group 1 IDH-mutant 1p/19q-codeleted oligodendrogliomas, the TERT-WT group had significantly worse overall survival than the TERT-MUT group (HR: 2.72, 95% CI 1.05-7.04, p = 0.04). In both Group 2, IDH-mutant astrocytomas and Group 3, IDH-mutant glioblastomas, neither TERT mutations nor ATRX alterations were significantly associated with survival. Among Group 4, IDH-wildtype glioblastomas, ATRX alterations were associated with favorable outcomes (HR: 0.36, 95% CI 0.17-0.81, p = 0.01). Among Group 5, IDH-wildtype astrocytomas, the TERT-WT group had significantly better overall survival than the TERT-MUT group (HR: 0.48, 95% CI 0.27-0.87), p = 0.02). Thus, we present evidence that in certain WHO 2016 diagnostic groups, testing for TERT promoter mutations or ATRX alterations may provide additional useful prognostic information.

Residual Deep Convolutional Neural Network Predicts MGMT Methylation Status.

Predicting methylation of the O6-methylguanine methyltransferase (MGMT) gene status utilizing MRI imaging is of high importance since it is a predictor of response and prognosis in brain tumors. In this study, we compare three different residual deep neural network (ResNet) architectures to evaluate their ability in predicting MGMT methylation status without the need for a distinct tumor segmentation step. We found that the ResNet50 (50 layers) architecture was the best performing model, achieving an accuracy of 94.90% (+/- 3.92%) for the test set (classification of a slice as no tumor, methylated MGMT, or non-methylated). ResNet34 (34 layers) achieved 80.72% (+/- 13.61%) while ResNet18 (18 layers) accuracy was 76.75% (+/- 20.67%). ResNet50 performance was statistically significantly better than both ResNet18 and ResNet34 architectures (p < 0.001). We report a method that alleviates the need of extensive preprocessing and acts as a proof of concept that deep neural architectures can be used to predict molecular biomarkers from routine medical images.

P/Q- and N-type calcium-channel antibodies: Oncological, neurological, and serological accompaniments.

INTRODUCTION: Voltage-gated calcium-channel autoimmunity (VGCC-P/Q and VGCC-N types) occurs beyond Lambert-Eaton syndrome and lung cancer. METHODS: We reviewed records for 236 Mayo Clinic patients with VGCC antibodies found in evaluation for paraneoplastic neurological autoimmunity (generally without myasthenic syndromes). RESULTS: VGCC autoantibodies were detected in 3.4% of neurological patients, 1.7% of healthy controls, and 4% of neurologically asymptomatic lung cancer controls. Fifty neurological patients (21%) had ≥ 1 neoplasm, historically (46) or detected prospectively [small-cell lung carcinoma (2), breast adenocarcinoma (2), lymphoma (1), and suspected tonsillar carcinoma (1)]. Autoimmune neurological diagnosis frequencies (encephalopathy, ataxia, myelopathy, neuropathy, neuromuscular junction disorder, and myopathy) among patients with medium values (24%; 0.10-0.99 nmol/L) or low values (19%; 0.03-0.10 nmol/L) were fewer than among patients with antibody values exceeding 1.00 nmol/L (71%; P = 0.02 and 0.004, respectively). CONCLUSIONS: Among neuronal VGCC-autoantibody-seropositive patients, autoimmune neurological phenotypes and cancer types are diverse. Cautious interpretation of results (particularly medium and low values) is advised. Muscle Nerve, 2016 Muscle Nerve 54: 220-227, 2016.

Seizures in patients with primary brain tumors: what is their psychosocial impact?

Seizures occur in most patients with primary malignant tumors and are associated with poor quality of life. To our knowledge, no previous studies have sought descriptions of quality of life in patients' own words. Patients with a history of a malignant primary brain tumor and seizures participated in semi-structured interviews, which were analyzed with qualitative methodology. Twenty-seven patients participated, most with high grade brain tumors. Most were receiving anti-seizure medication. Three distinct themes emerged: (1) the first seizure as a sentinel event, as manifested in part by how patients described their first seizure in remarkable detail ("I clearly remember the date…"); (2) seizures as inextricably tied to the brain tumor itself; for example, one patient explained how he "always wondered what was happening with my brain tumor" with each seizure; and (3) adaptation and acceptance-or lack therefore-to seizures. With respect to this third theme, patients conveyed frustration from an inability to work, to drive, and to take care of their children ("It's like you are 15 all over again.") Others described frustration with taking antiseizure medications ("I felt like an 80 year old, now taking her pills every day"). However, some patients had adapted or resigned themselves ("…so much of life is out of control-you just gotta take what you get."). These findings have future research implications but should also serve to make healthcare providers more aware of the heavy emotional burden that seizures thrust upon brain tumor patients.

Socioeconomic status and glioblastoma risk: a population-based analysis.

PURPOSE: Socioeconomic status (SES) is associated with risk of various cancer types because of correlation between SES and causal factors or increased case ascertainment, or both. Studies evaluating the association between glioblastoma and occupational or SES factors have yielded inconsistent results. We evaluated the association between SES and glioblastoma risk using a large, population-based cancer registry dataset. METHODS: Data of the Surveillance, Epidemiology, and End Results Program were used to evaluate the impact of SES on glioblastoma risk. SES was divided into quintiles on the basis of census tract of residence. Census tracts are small, geographically defined areas with relatively homogeneous population characteristics. RESULTS: Higher SES was strongly associated with increased risk of glioblastoma (p < .001). Relative to persons living in census tracts of the lowest SES quintile, the highest SES quintile had a rate ratio of 1.45 (95 % CI 1.39-1.51) (p < .001). Similar associations were seen in population subgroups defined by age, sex, and race. CONCLUSIONS: The strong association between higher SES and greater glioblastoma risk is unlikely to represent an ascertainment effect because glioblastoma is rapidly progressive and ultimately fatal. A number of previously proposed glioma risk factors may be correlated with SES, including atopy and allergy rates, cellular telephone use, and body morphometric measures. Further research is needed to define the mechanism of this association.

Exploring primary brain tumor patient and caregiver needs and preferences in brief educational and support opportunities.

PURPOSE: A primary brain tumor patient and caregiver survey was completed to investigate interest in brief support opportunities, focused on education, memory training, and healthy coping, during a routine clinical visit and at 3-month follow-up. METHODS: Patients with primary brain tumors receiving care in the Radiation Oncology Department at Mayo Clinic Rochester and their caregivers were recruited to complete the survey between June 2008 and September 2009. RESULTS: Both patients and their caregivers expressed greatest interest in education about brain tumors and cognitive effects of treatment. Interest in support opportunities targeting education, memory training, or healthy coping was low to modest. Bimodal distributions were found for almost all the support opportunities, revealing subgroups of patients and caregivers with high interest in such sessions. Overall, ratings of interest did not differ over time. CONCLUSIONS: Patients with primary brain tumors and their caregivers expressed most interest in education about their disease and potential cognitive effects of treatment. It appears that subgroups of patients and caregivers have very high interest in brief support opportunities. Identifying these subgroups of patients and families will allow targeted interventions focused on their needs and make the best use of limited resources.

Pilot evaluation of Scrambler therapy for the treatment of chemotherapy-induced peripheral neuropathy.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN), a common side effect of chemotherapy, needs better effective treatments. Preliminary data support the use of Scrambler therapy, a device which treats pain via noninvasive cutaneous electrostimulation, for the treatment of CIPN. The current manuscript reports data from a pilot trial, performed to investigate the effect of Scrambler therapy for the treatment of established CIPN. METHODS: Eligible patients had CIPN symptoms of ≥1 month duration with tingling and/or pain ≥4/10 during the prior week. Patients were treated with Scrambler therapy to the affected area(s) for up to ten daily 30-min sessions. Symptoms were monitored using a neuropathy questionnaire consisting of numerical analog scales ranging from 0 to 10, daily before therapy as well as weekly for 10 weeks after therapy. Descriptive summary statistics formed the basis of data analysis. RESULTS: Thirty-seven patients were enrolled. Twenty-five patients were treated primarily on their lower extremities while 12 were treated primarily on their upper extremities. There was a 53 % reduction in pain score from baseline to day 10; a 44 % reduction in tingling; and a 37 % reduction in numbness. Benefit appeared to last throughout 10 weeks of follow-up. There were no substantial adverse events. CONCLUSION: Preliminary data support that Scrambler therapy may be effective for the treatment of CIPN: a prospective placebo-controlled clinical trial should be performed.

Analysis of 60 reported glioma risk SNPs replicates published GWAS findings but fails to replicate associations from published candidate-gene studies.

Genomewide association studies (GWAS) and candidate-gene studies have implicated single-nucleotide polymorphisms (SNPs) in at least 45 different genes as putative glioma risk factors. Attempts to validate these associations have yielded variable results and few genetic risk factors have been consistently replicated. We conducted a case-control study of Caucasian glioma cases and controls from the University of California San Francisco (810 cases, 512 controls) and the Mayo Clinic (852 cases, 789 controls) in an attempt to replicate previously reported genetic risk factors for glioma. Sixty SNPs selected from the literature (eight from GWAS and 52 from candidate-gene studies) were successfully genotyped on an Illumina custom genotyping panel. Eight SNPs in/near seven different genes (TERT, EGFR, CCDC26, CDKN2A, PHLDB1, RTEL1, TP53) were significantly associated with glioma risk in the combined dataset (P < 0.05), with all associations in the same direction as in previous reports. Several SNP associations showed considerable differences across histologic subtype. All eight successfully replicated associations were first identified by GWAS, although none of the putative risk SNPs from candidate-gene studies was associated in the full case-control sample (all P values > 0.05). Although several confirmed associations are located near genes long known to be involved in gliomagenesis (e.g., EGFR, CDKN2A, TP53), these associations were first discovered by the GWAS approach and are in noncoding regions. These results highlight that the deficiencies of the candidate-gene approach lay in selecting both appropriate genes and relevant SNPs within these genes.

Carcinoembryonic antigen-expressing oncolytic measles virus derivative in recurrent glioblastoma: a phase 1 trial.

Measles virus (MV) vaccine strains have shown significant preclinical antitumor activity against glioblastoma (GBM), the most lethal glioma histology. In this first in human trial (NCT00390299), a carcinoembryonic antigen-expressing oncolytic measles virus derivative (MV-CEA), was administered in recurrent GBM patients either at the resection cavity (Group A), or, intratumorally on day 1, followed by a second dose administered in the resection cavity after tumor resection on day 5 (Group B). A total of 22 patients received study treatment, 9 in Group A and 13 in Group B. Primary endpoint was safety and toxicity: treatment was well tolerated with no dose-limiting toxicity being observed up to the maximum feasible dose (2×107 TCID50). Median OS, a secondary endpoint, was 11.6 mo and one year survival was 45.5% comparing favorably with contemporary controls. Other secondary endpoints included assessment of viremia, MV replication and shedding, humoral and cellular immune response to the injected virus. A 22 interferon stimulated gene (ISG) diagonal linear discriminate analysis (DLDA) classification algorithm in a post-hoc analysis was found to be inversely (R = -0.6, p = 0.04) correlated with viral replication and tumor microenvironment remodeling including proinflammatory changes and CD8 + T cell infiltration in post treatment samples. This data supports that oncolytic MV derivatives warrant further clinical investigation and that an ISG-based DLDA algorithm can provide the basis for treatment personalization.

Potassium channel complex autoimmunity induced by inhaled brain tissue aerosol.

OBJECTIVE: To test the hypothesis that autoimmunity induced by inhalation of aerosolized brain tissue caused outbreaks of sensory-predominant polyradiculoneuropathy among swine abattoir employees in the Midwestern United States. METHODS: Mice were exposed intranasally, 5 days per week, to liquefied brain tissue. Serum from exposed mice, patients, and unaffected abattoir employees were analyzed for clinically pertinent neural autoantibodies. RESULTS: Patients, coworkers, and mice exposed to liquefied brain tissue had an autoantibody profile dominated by neural cation channel immunoglobulin Gs (IgGs). The most compelling link between patients and exposed mice was magnetic resonance imaging (MRI) evidence of grossly swollen spinal nerve roots. Autoantibody responses in patients and mice were dose-dependent and declined after antigen exposure ceased. Autoantibodies detected most frequently, and at high levels, bound to detergent-solubilized macromolecular complexes containing neuronal voltage-gated potassium channels ligated with a high affinity Kv1 channel antagonist, 125I-α-dendrotoxin. Exposed mice exhibited a behavioral phenotype consistent with potassium channel dysfunction recognized in drosophila with mutant ("shaker") channels: reduced sensitivity to isoflurane-induced anesthesia. Pathological and electrophysiological findings in patients supported peripheral nerve hyperexcitability over destructive axonal loss. The pain-predominant symptoms were consistent with sensory nerve hyperexcitability. INTERPRETATION: Our observations establish that inhaled neural antigens readily induce neurological autoimmunity and identify voltage-gated potassium channel complexes as a major immunogen.

Striational antibodies in a paraneoplastic context.

INTRODUCTION: The clinical significance of striational antibodies (StrAbs) detected in the course of paraneoplastic antibody testing is unknown. METHODS: We compared all 203 striational antibody (StrAb)-seropositive patients identified (2004-2005) during evaluation for paraneoplastic antibodies with age- and sex-matched seronegative controls. RESULTS: Thymoma and myasthenia gravis (MG) were significantly more common among cases (P<0.0001). Cancers more rarely detected after StrAb detection were adenocarcinoma in 5 patients and sarcoma in 3 patients. All patients who had a cancer identified after StrAb testing had a titer of ≥ 1:7680 or a coexisting muscle AChR-binding antibody. Autoimmune disorders more commonly observed among cases (with any StrAb value) included: hypothyroidism; rheumatoid arthritis; and pernicious anemia (all P<0.05). CONCLUSIONS: StrAbs may serve as a diagnostic clue for an autoimmune diagnosis. There is a low likelihood of oncological significance in patients with StrAb titers <1:7680 without coexisting paraneoplastic Abs.

Gliomatosis cerebri: clinical characteristics, management, and outcomes.

Gliomatosis cerebri is a rare diffusely infiltrating primary neoplastic glial process of the brain. Our objective is to review clinical presentation, management, and outcome in a large single institution series of gliomatosis cerebri patients. 54 consecutive gliomatosis cerebri cases presenting to Mayo Clinic Rochester between 1991 and 2008 were retrospectively reviewed. Inclusion criteria included involvement of at least three cerebral lobes, lack of a single discrete mass and pathological confirmation of diffuse glioma. Median overall survival (OS) was 18.5 months. Age, gender, presenting symptoms, and contrast enhancement did not correlate significantly with survival, though there was a trend toward decreased overall survival in patients above the median age of 46 years. Karnofsky performance score <70 was associated with poor OS (median 9.5 vs. 20.5 months, p = 0.02). Higher histologic grade was associated with poor progression-free survival (PFS; median for WHO grades II, III, and IV: 21.5, 6.5, and 4 months; p = 0.03) and OS (median 34, 15.5, and 8.5 months; p < 0.05). Radiation therapy was strongly associated with better prognosis (PFS 16.5 vs. 4.5 months, p < 0.01; OS 27.5 vs. 6.5, p < 0.01), but chemotherapy was not. Gliomatosis cerebri patients have a poor prognosis. Lower KPS upon presentation and higher histologic grade predict decreased survival. Surgery's role is limited beyond biopsy for diagnostic purposes. Radiotherapy appears beneficial, although selection bias could be present in this retrospective study. Chemotherapy's value is not as clear but this must be interpreted with caution given variable treatment regimens in this series.

Management and Long-Term Outcomes of Patients With Recurrent Stroke-Like Episodes After Cranial Radiotherapy.

BACKGROUND: Recurrent Stroke-Like Episodes of transient negative neurologic symptoms are a long-term consequence of cranial radiation therapy (RT) that may lead to significant functional impairment and worsen quality of life. We assessed management patterns and clinical course at our institution to assess optimal management strategy and understand long-term outcomes. METHODS: We conducted a retrospective review of all patients with recurrent negative neurologic symptoms after cranial RT who were treated at Mayo Clinic (Rochester), with follow-up extending through October 2021 with a goal of assessing for clinical change in the setting of medical management. Descriptive statistics and Fisher exact tests were performed for group comparisons. RESULTS: Twenty-five patients were included. Median age at diagnosis was 28.7 years (range: 3.0 to 65.8). Median time from RT to symptom onset was 14.6 years (range: 3.3 to 30.5). The most common presentations included hemiparesis (56%), visual field (33%) and hemisensory (22%) loss, and aphasia (22%). Therapeutics used specifically for management of recurrent episodes included antiseizure medications (92%), antiplatelets (68%), verapamil (52%), statins (48%), glucocorticoids (24%), antivirals (20%), and angiotensin converting enzyme inhibitor/ Angiotensin receptor blockers (16%). Antivirals were less commonly used in patients with cessation (Fisher exact, P =0.0235). Progressive encephalopathy was more commonly seen in those without cessation (Fisher exact, P =0.0072), and in all patients who died at last follow-up. CONCLUSIONS: Although retrospective experience from a single institution, our cohort represents one of the largest with management data reported for this complex clinical scenario. We hope that our findings may be used as a reference for clinicians in the management of this challenging clinical scenario.